Pharmaceutical liquid compositions of meloxicam

ABSTRACT

The present invention relates to stable injectable compositions comprising meloxicam or its pharmaceutically acceptable salts, solvates, or hydrates thereof, wherein the composition is provided in a sealed container, e.g., an ampoule, vial and pre-filled syringe. Further, the present invention relates to a stable injectable solution comprising meloxicam or its pharmaceutically acceptable salts, solvates, or hydrates thereof, suitable for subcutaneous, intravenous or intramuscular administration. The invention relates to methods for manufacturing stable injectable solutions of meloxicam. The present invention further relates to a method of treating pain by parenterally administering to a patient in need thereof a composition comprising a stable solution of meloxicam, wherein said solution provides rapid onset of action for pain relief compared to a reference composition.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.17/368,367 filed on Jul. 6, 2021, which claims priority to foreignApplication No. IN, 202041028641 filed on Jul. 6, 2020, which isincorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to stable injectable compositionscomprising meloxicam or its pharmaceutically acceptable salts, solvates,or hydrates thereof, wherein the composition is provided in a sealedcontainer, e.g., an ampoule, vial and pre-filled syringe. Further, thepresent invention relates to a stable injectable solution comprisingmeloxicam or its pharmaceutically acceptable salts, solvates, orhydrates thereof, suitable for subcutaneous, intravenous orintramuscular administration. The invention further relates to methodsfor manufacturing stable injectable solutions of meloxicam.

BACKGROUND OF THE INVENTION

Meloxicam, an oxicam derivative, is a member of the enolic acid group ofnonsteroidal anti-inflammatory drugs (NSAIDs). It is reported to be aselective inhibitor of cyclo-oxygenase-2 (COX-2) and exerts potentanti-inflammatory, anti-rheumatism and anti-pyretic activity. Thechemical name of meloxicam is4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carbox-amide-1,1-dioxideand its chemical structure is represented by the structural Formula (I).

Meloxicam is practically insoluble in water, with higher solubilityobserved in strong acids and bases. It is very slightly soluble inmethanol. Meloxicam has been approved for relieving signs and symptomsof osteoarthritis, relieving the signs and symptoms of rheumatoidarthritis, and treatment of lower back pain. Meloxicam is especiallyeffective for treatment of all types of pain associated withinflammation.

Non-steroidal anti-inflammatory drugs (NSAIDs) like meloxicam, areuseful in pain management because NSAIDs provide an analgesic effectwithout the sedation and addictive properties of narcotic analgesics.Furthermore, the long half-life of meloxicam makes it useful forlong-lasting relief which is not provided by narcotic or opioidanalgesics. However, due to their typically long onset of action,conventional NSAIDs, including meloxicam, are frequently inappropriatefor management of acute pain.

The form of meloxicam earlier approved and marketed in the United Statesis MOBIC®, provided as 7.5 and 15 mg tablets. Mobic® is approved forrelieving the signs and symptoms of osteoarthritis and rheumatoidarthritis. Meloxicam when administered orally has a slow onset ofanalgesic action, largely due to poor water solubility. It is thereforeabsorbed with a time delay after administration. It has a prolongedabsorption, with the time of maximum observed plasma concentration(T_(max)) approximately 5-6 hours following oral administration, whichis consistent with its poor aqueous solubility. Although meloxicam hasan analgesic effect without sedation and addictive properties ofnarcotic analgesics, due to prolonged absorption in gastrointestinaltract and delayed onset of action and longer T_(max), meloxicam ishampered to treat acute pain i.e., management of moderate-to-severepost-operative pain by oral administration.

Injectable formulations containing meloxicam are very challenging tomanufacture as meloxicam is an insoluble drug displaying poor solubilitycharacteristics. One means of addressing this challenge is to prepare aninjectable dispersion which does not require complete solubilization ofmeloxicam.

Recently, an injectable formulation of meloxicam was approved by UnitedStates Food and Drug Administration (USFDA) under the brand name ANJESO®for the management of moderate-to-severe pain, alone or in combinationwith non-NSAID analgesics in adults. ANJESO® is formulated as an aqueousdispersion containing 30 mg/mL of meloxicam per vial. Anjeso® is aninjectable formulation of meloxicam for the intravenous (IV) route ofadministration that uses a proprietary Nano Crystal® ColloidalDispersion (NCD) technology. ANJESO®was approved by the USFDA under NewDrug Application (NDA) Number 210583 and National Drug Code (NDC) Number71518-001. Each mL of aqueous dispersion of ANJESO® contains 30 mg ofmeloxicam, 9 mg povidone, 3 mg sodium deoxycholate, 60 mg sucrose, andwater for injection (herein after called as reference composition).

The recommended dose of ANJESO® is 30 mg once daily, administered asintravenous bolus injection over 15 seconds. However, ANJESCO® providesmeaningful pain relief within a median time of only 2-3 hr afteradministration; it may not be useful in cases where a rapid onset ofpain relief is required. Thus, it is desirable to have a non-NSAIDanalgesic with a rapid onset of effect for providing immediate relief ofpain.

The in vivo performance of meloxicam when formulated as a dispersion forintravenous administration will be sensitive to variations in particlesize distribution, particle agglomeration, particle charge (zetapotential), crystalline state, particle morphology, dose uniformity andrate of dissolution of particles in blood plasma. Injectable dispersionsare also fundamentally unstable and it is difficult to ensure that thephysical stability of the formulation is retained over the entire periodof the shelf-life. These factors influence the quality & efficacy offinished product, which makes injectable dispersions being lesspreferred by physicians. Another drawback of injectable dispersion ofmeloxicam is the time it takes to provide a meaningful pain relief,which is 2 to 3 hours after administration.

The size reduction techniques to obtain smaller particles of meloxicamutilize complicated processes which are often cost intensive. Sizereduction of the meloxicam require many steps like multiple crushing,milling and pulverizing. In general, the size reduction machinery ismassive, expensive and energy intensive and such units sufferunavoidable wear and tear that incurs substantial operational andmaintenance costs. Use of such massive machinery and other specificrequirements of the process for making such particles, further add up tothe cost of manufacturing the drug formulation.

Because of the problems associated with the currently approved productsof meloxicam, it is always desirable to develop an injectable meloxicamsolution for human use, which is safe, therapeutically effective andeasy to administer.

There exists a need for development of novel compositions of meloxicamthat are ready-to-use or ready-to-dilute, and which minimizes orprevents degradation of meloxicam. There exists a need for developingstable, therapeutically effective, ready-to-use or ready-to-diluteinjectable solutions of meloxicam suitable for human use.

It is further desirable to develop injectable meloxicam solution forhuman use which displays rapid onset of action and provides fasterrelief of pain, compared to the currently approved and marketed dosageforms of meloxicam.

It would also be desirable for inventive meloxicam solutions to remainstable over relevant period of time under suitable storage conditionsand to be suitable for administration by intravenous or other parenteralroutes.

Preparing a stable injectable solution of meloxicam is quite challengingdue to the inherent poor solubility characteristics exhibited bymeloxicam. Attempts have been made earlier in order to formulate stableinjectable solution of meloxicam. However, until now, none of them havebeen successful in developing a stable injectable solution of meloxicam,particularly because of the poor solubility exhibited by meloxicam inaqueous solvents.

The present invention fulfils this need by developing novel injectablesolutions of meloxicam and providing methods of efficient and safer useto achieve an improved standard of patient care.

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to novel injectablesolution of meloxicam, suitable for human use, for the prevention,treatment or management of acute or chronic pain.

In another aspect, the present invention relates to pharmaceuticalcompositions of meloxicam, suitable for human use, displaying rapidonset of action and providing faster relief of pain.

An aspect of the present invention relates to injectable solution ofmeloxicam and methods for preparing the compositions.

An aspect of the present invention relates to injectable solution ofmeloxicam, suitable for human use, for the prevention, treatment ormanagement of moderate-to-severe pain.

In certain aspects, the inventive pharmaceutical compositions aresuitable for subcutaneous, intravenous or intramuscular administration.

An aspect of the present invention relates to injectable solution ofmeloxicam suitable for intravenous administration.

In certain aspects, the inventive pharmaceutical compositions ofmeloxicam are suitable for intravenous bolus administration orintravenous infusion administration.

The inventive pharmaceutical compositions according to the invention maybe provided in the form of aqueous or non-aqueous solution.

In another aspect of the present invention relates to pharmaceuticalcompositions of meloxicam for human use, suitable for intravenousadministration, displaying rapid onset of action and providing fasterrelief of pain, compared to the currently approved and marketed dosageforms of meloxicam.

In another aspect, the inventive pharmaceutical compositions areprovided in a sealed container selected from ampoules, vials andpre-filled syringes, preferably a sealed pre-filled syringe.

The inventive compositions are advantageously ready-to-use (RTU) orready-to-dilute (RTD). An aspect of the invention relates to stableready-to-use or ready-to-dilute meloxicam compositions suitable forintravenous administration.

Another aspect relates to stable ready-to-use or ready-to-dilute, liquidcompositions of meloxicam, comprising one or more solvents andoptionally one or more pharmaceutically acceptable excipients.

Yet another aspect of the present invention relates to solutions ofmeloxicam are suitable for intravenous administration, displaying rapidonset of action and providing faster relief of pain, compared to thecurrently approved and marketed dosage forms of meloxicam.

In an aspect, solutions suitable for intravenous administrationcomprises (a) therapeutically effective amount of meloxicam, (b)pharmaceutically acceptable solvent; and (c) one or morepharmaceutically acceptable excipients.

In an aspect, stable solutions suitable for intravenous administrationcomprises (a) therapeutically effective amount of meloxicam, (b)pharmaceutically acceptable solvent; and (c) one or morepharmaceutically acceptable excipients.

In an aspect, stable injectable solutions suitable for intravenousadministration comprises (a) therapeutically effective amount ofmeloxicam, (b) pharmaceutically acceptable solvent; and (c) optionally,one or more pharmaceutically acceptable excipients.

In another aspect, stable injectable solutions suitable for intravenousadministration comprises (a) therapeutically effective amount ofmeloxicam, (b) pharmaceutically acceptable solvent; and (c) optionally,one or more pharmaceutically acceptable excipients, wherein meloxicam ispresent at a concentration of about 5 mg/mL or more.

In another aspect, stable injectable solutions suitable for intravenousadministration comprises (a) therapeutically effective amount ofmeloxicam, (b) pharmaceutically acceptable solvent; and (c) optionally,one or more pharmaceutically acceptable excipients, wherein meloxicam ispresent at a concentration of about 15 mg/mL or more.

In another aspect, stable injectable solutions suitable for intravenousadministration comprises (a) therapeutically effective amount ofmeloxicam, (b) pharmaceutically acceptable solvent; and (c) optionally,one or more pharmaceutically acceptable excipients, wherein meloxicam ispresent at a concentration of about 30 mg/mL or more.

In an aspect, stable injectable solutions of meloxicam suitable forintravenous administration comprises (a) therapeutically effectiveamount of meloxicam, (b) pharmaceutically acceptable solvent; and (c)optionally, one or more pharmaceutically acceptable excipients selectedfrom the group consisting of solubilizer, buffering agent, nucleationinhibiting agent, tonicity contributing agent, pH adjusting agent,antioxidant, chelating agent and preservative.

In an aspect, stable solutions of meloxicam suitable for intravenousadministration comprises (a) therapeutically effective amount ofmeloxicam, (b) pharmaceutically acceptable solvent; and (c) one or morepharmaceutically acceptable excipients selected from the groupconsisting of solubilizer, buffering agent, nucleation inhibiting agent,tonicity contributing agent, pH adjusting agent, antioxidant, chelatingagent and preservative.

In an aspect, stable solutions of meloxicam suitable for intravenousadministration comprises (a) therapeutically effective amount ofmeloxicam, (b) pharmaceutically acceptable solvent; (c) one or moresolubilizers; and (d) optionally, one or more other pharmaceuticallyacceptable excipients.

In an aspect, stable solutions of meloxicam suitable for parenteraladministration comprises (a) therapeutically effective amount ofmeloxicam, (b) pharmaceutically acceptable solvent; (c) one or moresolubilizers; and (d) one or more nucleation inhibitors e) optionally,one or more other pharmaceutically acceptable excipients.

In an aspect, stable solutions of meloxicam suitable for intravenousadministration comprises (a) therapeutically effective amount ofmeloxicam, (b) one or more solvent (c) one or more solubilizer; and (d)one or more nucleation inhibitor e) optionally, one or more otherpharmaceutically acceptable excipients.

In another aspect, stable solutions of meloxicam suitable forintravenous administration comprises (a) therapeutically effectiveamount of meloxicam, (b) pharmaceutically acceptable solvent; (c) one ormore solubilizers; and (d) optionally, one or more otherpharmaceutically acceptable excipients, wherein concentration of thesolubilizer ranges from about 2.5 mg/mL to about 400 mg/mL.

In another aspect, stable solutions of meloxicam suitable forintravenous administration comprises (a) therapeutically effectiveamount of meloxicam, (b) pharmaceutically acceptable solvent; (c) one ormore solubilizers; and (d) optionally, one or more otherpharmaceutically acceptable excipients, wherein the solution has a pH inthe range of about 5 to about 12.

In another aspect, stable solutions of meloxicam suitable forintravenous administration comprises (a) therapeutically effectiveamount of meloxicam, (b) pharmaceutically acceptable solvent; (c) one ormore solubilizers; and (d) optionally, one or more otherpharmaceutically acceptable excipients, wherein the solution is stablefor at least 6 months at 40° C./75% RH.

In another aspect, stable solutions of meloxicam suitable forintravenous administration comprises (a) therapeutically effectiveamount of meloxicam, (b) pharmaceutically acceptable solvent; (c) one ormore solubilizers; and (d) optionally, one or more otherpharmaceutically acceptable excipients, wherein the solution is stablefor at least 6 months at 25° C./60% RH.

In another aspect, stable solutions of meloxicam suitable forintravenous administration comprises (a) therapeutically effectiveamount of meloxicam, (b) pharmaceutically acceptable solvent; (c) one ormore solubilizers; and (d) optionally, one or more otherpharmaceutically acceptable excipients, wherein the solution is stablefor at least 12 months at 25° C./60% RH.

In another aspect, stable solutions of meloxicam suitable forintravenous administration comprises (a) therapeutically effectiveamount of meloxicam, (b) pharmaceutically acceptable solvent; (c) one ormore solubilizers; and (d) optionally, one or more otherpharmaceutically acceptable excipients, wherein the solution is stablefor at least 12 months at 2-8° C.

In certain aspects, the composition according to the invention is stablefor at least 3 months at 25° C. and 60% relative humidity. In certainembodiments, the composition according to the invention is stable for atleast 3 months at 40° C. and 75% relative humidity. In certainembodiments, the composition according to the invention is stable for atleast 24 months when stored under room temperature.

In another aspect, stable solutions of meloxicam suitable forintravenous administration comprises (a) therapeutically effectiveamount of meloxicam, (b) pharmaceutically acceptable solvent; (c) one ormore solubilizers; and (d) optionally, one or more otherpharmaceutically acceptable excipients, wherein the level of eachimpurity in the solution is less than about 2% w/w, preferably less thanabout 1.5% w/w, more preferably less than about 1% w/w, more preferablyless than about 0.5% w/w as measured by HPLC.

In another aspect, stable solutions of meloxicam suitable forintravenous administration comprises (a) therapeutically effectiveamount of meloxicam, (b) pharmaceutically acceptable solvent; (c) one ormore solubilizers; and (d) optionally, one or more otherpharmaceutically acceptable excipients, wherein in said stable solutionsof meloxicam was bioequivalent to a commercially available meloxicamdrug product Anjeso® (New Drug Application (NDA) Number 210583 andNational Drug Code (NDC) Number 71518-001).

In another aspect, stable solutions of meloxicam suitable forintravenous administration comprises (a) therapeutically effectiveamount of meloxicam, (b) pharmaceutically acceptable solvent; (c) one ormore solubilizers; and (d) optionally, one or more otherpharmaceutically acceptable excipients, wherein in said stable solutionsof meloxicam was bioequivalent to a commercially available 30mg/mLmeloxicam drug product Anjeso® (New Drug Application (NDA) Number 210583and National Drug Code (NDC) Number 71518-001).

In another aspect, stable solutions of meloxicam suitable forintravenous administration comprises (a) therapeutically effectiveamount of meloxicam, (b) pharmaceutically acceptable solvent; (c) one ormore solubilizers; and (d) optionally, one or more otherpharmaceutically acceptable excipients, wherein in said composition uponintravenous administration exhibits bioequivalence to a commerciallyavailable reference meloxicam drug product (such as Anjeso®), andwherein said bioequivalence is established by at least one of: (i) aconfidence interval for mean AUC₀₋₁ between about 80% and about 125%;(ii) a confidence interval for mean AUC_(0-infinity) between about 80%and about 125%; (iii) a confidence interval for mean C_(max) betweenabout 80% and about 125% or a combination thereof.

In an aspect, stable solutions of meloxicam suitable for intravenousadministration comprises (a) therapeutically effective amount ofmeloxicam, (b) one or more solvents (c) one or more solubilizers; and(d) one or more nucleation inhibitors e) optionally, one or more otherpharmaceutically acceptable excipients, wherein concentration of thesolubilizer ranges from about 2.5 mg/mL to about 400 mg/m L.

In an aspect, stable solutions of meloxicam suitable for intravenousadministration comprises (a) therapeutically effective amount ofmeloxicam, (b) one or more solvents (c) one or more solubilizers; and(d) one or more nucleation inhibitors e) optionally, one or more otherpharmaceutically acceptable excipients, wherein the solution has a pH inthe range of about 5 to about 10.

In an aspect, stable solutions of meloxicam suitable for intravenousadministration comprises (a) therapeutically effective amount ofmeloxicam, (b) one or more solvents (c) one or more solubilizers; and(d) one or more nucleation inhibitors e) optionally, one or more otherpharmaceutically acceptable excipients, wherein the solution is stablefor at least 6 months at 40° 0/75% RH.

In an aspect, stable solutions of meloxicam suitable for intravenousadministration comprises (a) therapeutically effective amount ofmeloxicam; (b) one or more solvents (c) one or more solubilizers; and(d) one or more nucleation inhibitors e) optionally, one or more otherpharmaceutically acceptable excipients, wherein the solution is stablefor at least 12 months at 25° 0/60% RH.

In an aspect, stable solutions of meloxicam suitable for intravenousadministration comprises (a) therapeutically effective amount ofmeloxicam, (b) one or more solvents (c) one or more solubilizers; and(d) one or more nucleation inhibitors e) optionally, one or more otherpharmaceutically acceptable excipients, wherein the level of eachimpurity in the solution is less than about 2% w/w, preferably less thanabout 1.5% w/w, more preferably less than about 1% w/w, more preferablyless than about 0.5% w/w, more preferably less than about 0.2% w/w asmeasured by HPLC.

In an aspect, stable solutions of meloxicam suitable for intravenousadministration comprises (a) therapeutically effective amount ofmeloxicam, (b) one or more solvents (c) one or more solubilizers; and(d) one or more nucleation inhibitors e) optionally, one or more otherpharmaceutically acceptable excipients, wherein in said composition uponparenteral administration exhibits bioequivalence to a commerciallyavailable reference meloxicam drug product (such as Anjeso®), andwherein said bioequivalence is established by at least one of: (i) aconfidence interval for mean AUC₀₋₁ between about 80% and about 125%;(ii) a confidence interval for mean AUC_(0-infinity) between about 80%and about 125%; (iii) a confidence interval for mean C_(max) betweenabout 80% and about 125% or a combination thereof.

Another aspect of the invention provides stable solutions of meloxicamsuitable for intravenous administration comprising (a) therapeuticallyeffective amount of meloxicam, (b) pharmaceutically acceptable solvent;(c) one or more solubilizers selected from arginine, lysine, meglumine,cyclodextrin derivative, diethanolamine, tromethamine or mixturesthereof; and (d) optionally, one or more other pharmaceuticallyacceptable excipients, wherein concentration of the solubilizer rangesfrom about 2.5 mg/mL to about 400 mg/mL.

Another aspect of the invention provides stable solutions of meloxicamsuitable for intravenous administration comprising (a) therapeuticallyeffective amount of meloxicam, (b) polyethylene glycol (c) meglumine,and (d) polyvinyl pyrrolidone e) optionally, one or more otherpharmaceutically acceptable excipients, wherein the solution has a pH inthe range of about 7 to about 10.

In certain aspects, the invention relates to methods for making acomposition, which comprise: (i) dispensing 60% v/v water for injection;(ii) adding one or more solubilizing agents to form a first solution;(iii) adding meloxicam to the first solution to form a second solution;and (iv) optionally, adjusting the pH of the second solution by adding asuitable acid or base, e.g., hydrochloric acid and/or sodium hydroxide(v) final volume was made with 40% v/v water for injection.

In certain aspects, the invention relates to methods for making acomposition, which comprise: (i) dispensing 60% v/v water for injection;(ii) adding one or more solubilizing agents to form a first solution;(iii) adding meloxicam to the first solution to form a second solution;(iv) adding nucleation inhibitor (v) adding one or moresolvents/co-solvents (vi) optionally, adjusting the pH of the secondsolution by adding a suitable acid or base, e.g., hydrochloric acidand/or sodium hydroxide and (vii) final volume was made with 40% v/vwater for injection.

An aspect of the present invention relates to a method of treating painby parenterally administering to a patient in need thereof a compositioncomprising a stable solution of meloxicam, wherein said solutionprovides rapid onset of action for pain relief compared to a referencecomposition.

An aspect of the present invention relates to the method as describedabove wherein said composition comprises meloxicam in a solubilizedform.

An aspect of the present invention relates to the method as describedabove wherein said composition comprises meloxicam, one or moresolubilizers; a nucleation inhibitor; one or more pharmaceuticallyacceptable solvents; and optionally one or more other pharmaceuticallyacceptable excipients.

An aspect of the present invention relates to the method as describedabove wherein the meloxicam dose is 30 mg.

An aspect of the present invention relates to the method as describedabove, wherein the solubilizer is selected from a group comprisingmeglumine, cyclodextrin, cyclodextrin derivative, monoethanolamine,diethanolamine, tromethamine, hydroxypropyl methyl cellulose (HPMC),L-arginine, L-lysine, polysorbate 80 (Tween® 80), polysorbate 20 (Tween®20), poloxamer, propylene glycol, glycerin, ethanol, polyethylene glycol(300 and 400), sorbitol, dimethylacetamide, and polyethoxylated castoroil (Cremophor® EL) or combinations thereof.

An aspect of the present invention relates to the method as describedabove, wherein the nucleation inhibitor is povidone.

An aspect of the present invention relates to the method as describedabove, wherein the administration of said composition provides thepatient a rapid onset of pain relief without the use of a second NSAID.

An aspect of the present invention relates to the method as describedabove, wherein said meloxicam solution stored for 1 month at 40° C./75%RH has an amount of 2-Amino-5-methylthiazole that is less than about0.2% w/w of meloxicam of the total composition.

An aspect of the present invention relates to the method as describedabove, wherein said composition stored for 6 months at 40° C./75% RH hasan amount of 2-Amino-5-methylthiazole that is less than about 0.2% w/wof meloxicam of the total composition.

An aspect of the present invention relates to the method as describedabove, wherein said composition stored for 1 month at 40° C./75% RH hasan amount of 2-Amino-5-methylthiazole that is less than about 0.2% w/wof meloxicam of the total composition.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is comparison of % change in average pain withdrawal latency inrats administered with test compounds (i.e., Vehicle control (0.9%saline), ketorolac tromethamine (3 mg/kg; IV), Anjeso® (3 mg/kg; IV),Composition K (3 mg/kg; IV).

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all the technical and scientific terms usedherein have the same meanings as commonly known by a person skilled inthe art. In the case that there is a plurality of definitions for theterms herein, the definitions provided herein will prevail.

As used herein, “a,” “an,” “the,” “at least one,” and “one or more” areused interchangeably. As used herein, the term “or” is generallyemployed in its usual sense including “and/or” unless the contentclearly dictates otherwise.

As used herein the term “meloxicam” refers to meloxicam free base or apharmaceutically acceptable salt, solvate or hydrate thereof. It alsoincludes geometric isomer or a stereoisomer thereof. In certain aspects,meloxicam free base may be used. Any crystalline form as well as theamorphous form of meloxicam may be used for the preparation ofpharmaceutical compositions of the present invention.

The terms “about” and “approximate”, when used along with a numericalvariable, generally means the value of the variable and all the valuesof the variable within an experimental error (e.g., 95% confidenceinterval for the mean) or within a specified value ±10% or within abroader range.

Within the context of the present invention, the term “ready-to-use” or“RTU” as used herein refers to an injectable composition that is stableand is not reconstituted from a lyophilizate. The term “ready-to-use” or“RTU” also encompasses within its scope, injectable compositions thatare stable and does not require any reconstitution or dilution withparenterally acceptable diluent and can be directly administered to thepatient.

Within the context of the present invention, the term “ready-to-dilute”or “RTD” as used herein refers to an injectable composition that isstable and is diluted with a suitable diluent for parenteraladministration.

The terms “composition”, “pharmaceutical composition”, “pharmaceuticalproduct”, “dosage form”, “pharmaceutical dosage form”, “formulation”,“pharmaceutical formulation”, etc., refer to a pharmaceuticalcomposition that may be administered to a patient in need of treatment,which may be in any conventional formulation. For example, the term“pharmaceutical composition” as used herein refers to a solution.

Within the context of this invention, the term “solution” refers to amixture of one or more substances dispersed molecularly (i.e.,dissolved) in a dissolving liquid medium or vehicle. The solution ispreferably homogeneous, in the sense that the active pharmaceuticalingredient (API) is essentially uniformly distributed and concentratedin the solution. The liquid solution may be viscous or not. A solutiondiffers from a suspension which comprises solid particles dispersedthroughout a liquid phase in which they are not soluble. As used herein,the term “solution” further means a solution which does not contain anyvisible particulate matter, solid particle, liposome or nanoparticles.The solution provides % transmittance, when measured 650 nm, not lessthan 97 examples, not less than 98%, less than 99%, not less than 99.5%,not less than 99.6%, not less than 99.7% or not less than 99.8%.

The term “parenterally acceptable liquid vehicle”, “vehicle”, “solvent”and “parenterally acceptable liquid solvent” are interchangeable.

The term “pharmaceutically acceptable excipient” as used herein means adiluent, carrier, or composition auxiliary, which is non-toxic andinert, which does not have undesirable effects on a subject to whom itis administered and is suitable for delivering a therapeutically activeagent to the target site without affecting the therapeutic activity ofthe said active agent.

The terms “stable” and “stability” mean that the evolution of theproduct with time and/or under specific environmental conditions (i.e.,temperature, humidity, etc.) has no significant effects on its quality,safety and/or efficacy for a given time period. It can be measuredthrough the formation of degradation products (impurities), variation ofpH, appearance (precipitation), microbial growth, and/or colour. Theterm “stable” indicates both chemical and physical stability. The term“stable” can further mean as no more than about a 5% loss of meloxicamunder typical commercial storage conditions. Preferably, formulations ofthe present inventions will have no more than about a 3% loss ofmeloxicam, more preferably, no more than about a 2% loss of melphalan,under typical commercial storage conditions.

The term “degradation product,” as used herein, refers to an unwantedchemical or impurity (including, but not limited to known or unknownrelated substances) that can develop during the manufacturing,transportation, and storage of drug products and can affect the efficacyof pharmaceutical products. It can form in response to changes in light,temperature, pH, and humidity, or due to inherent characteristics ofactive ingredient, such as their reaction with excipients or on contactwith the packaging.

The term “parenteral” or “injectable” refers to routes selected fromsubcutaneous (SC), intravenous (IV), intramuscular (IM), intradermal(ID), intraperitoneal (IP) and the like.

The expression “bioequivalent” or “bioequivalence” is a term of art andis intended to be defined in accordance with Approved Drug Products withTherapeutic Equivalence Evaluations, 41^(th) Edition, which is publishedby the U.S. Department of Health and Human Services, and is commonlyknown as the “Orange Book”. Generally, bioequivalence can be defined asthe absence of significant difference in the rate and extent to whichthe active ingredient or active moiety in pharmaceutical equivalents orpharmaceutical alternatives becomes available at the site of drug actionwhen administered at the same molar dose under similar conditions in anappropriately designed study. Bioequivalence of different formulationsof the same drug substance involves equivalence with respect to the rateand extent of drug absorption. The pharmacokinetic characteristics ofthe concentration-time curve, such as the maximum observed plasmaconcentration (C_(max)), the time to reach C_(max), and the area underthe plasma concentration versus time curve (AUC), are examined bystatistical procedures which are well-established in the field ofpharmacokinetics. Two formulations whose rate and extent of absorptiondiffer by −20%/+25% or less are generally considered to bebioequivalent.

The term “bolus dose” refers to a discrete amount of a medication or adrug, e.g., meloxicam, which is given within a specific time. Thespecific time over which the bolus dose is administered (also referredto herein as the infusion rate) may be any suitable time which providesrapid onset of action (i.e., pain relief) and which does not causesignificant injection site pain, such as a significant burningsensation. In some embodiments, the infusion time may be about 1 minuteor less.

The term “in vivo” in general means in the living body of a plant oranimal, whereas the term “in vitro” generally means outside the body andin an artificial environment.

The term “subject” refers to an animal, including a human or non-human.The terms patient and subject may be used interchangeably herein.Non-human may be a rat, a dog, a mice or a guinea pig.

The term “peak time of plasma drug concentration (T_(max))” means thetime when peak plasma drug concentration (C_(max)) is attained afterdrug administration.

The term “peak plasma drug concentration (C_(max))” means the maximumplasma drug concentration attained after drug administration.

The term “AUC_(0-infinity)” means the area under a plasma drugconcentration—time curve from time point of 0 to infinity after drugadministration.

The term “AUC_(0-t)” means the area under a plasma drugconcentration—time curve from time point of 0 to t after drugadministration, wherein t is time in hours and is in between 1 hour to72 hours.

The term “shelf life” means the period beginning from manufacture of aformulation beyond which the formulation cannot be expected beyondreasonable doubt to yield the therapeutic outcome approved by agovernment regulatory agency.

As used herein, the term “storage” refers to the holding of acomposition under controlled or uncontrolled conditions for a periodranging from a few minutes to several months or longer. Storageconditions that can be controlled include, for example, temperature,humidity, and the level of light. In many cases, storage of apharmaceutical formulation is under industry acceptable standards and/orstandards that are mandated by regulatory agencies, such as USFDA.

By “therapeutically effective” amount is meant the amount of a drugsufficient to treat, prevent, or ameliorate a condition in a subject orpatient. The effective amount of meloxicam, used to practice the presentinvention for therapeutic management of a condition may be determinedand adjusted by a person of ordinary skill to provide the appropriateamount and dosage regimen, e.g., depending upon one or more of themanner of administration, the age, body weight, sex, and/or generalhealth of the patient.

As used herein, “to treat” a condition or “treatment” of the conditionis an approach for obtaining beneficial or desired results, such asclinical results. Beneficial or desired results can include, but are notlimited to, alleviation or amelioration of one or more symptoms orconditions; diminishment of extent of disease, disorder, or condition;stabilized (i.e., not worsening) state of disease, disorder, orcondition; preventing spread of disease, disorder, or condition; delayor slowing the progress of the disease, disorder, or condition;amelioration or palliation of the disease, disorder, or condition; andremission (whether partial or total), whether detectable orundetectable. “Palliating” a disease, disorder, or condition means thatthe extent and/or undesirable clinical manifestations of the disease,disorder, or condition are lessened and/or time course of theprogression is slowed or lengthened, as compared to the extent or timecourse in the absence of treatment.

The objective of the present invention is to increase the solubility ofmeloxicam enabling formulation of meloxicam solution dosage form.Another objective of the present invention is to provide stable aqueoussolutions of meloxicam having long-term storage stability.

The inventive pharmaceutical compositions described herein may beprovided in the form of a solution suitable for injection. To preparesuch composition, active drug is dissolved in a parenterally acceptableliquid vehicle. In certain non-limiting embodiments, meloxicamcomposition is formulated as a liquid and provided in the form of asolution. The pharmaceutically acceptable liquid vehicle or solvent maycomprise water, water for injection, saline, dextrose solution, alcohol,ethanol, glycerine, polyol (for example, propylene glycol, andpolyethylene glycol, and the like), dimethylacetamide,N-methylpyrollidone, dimethyl sulfoxide, ringer's solution, isotonicsodium chloride solution, or suitable mixtures thereof.

The inventive pharmaceutical compositions of the present invention maycontain suitable pharmaceutically acceptable solvents or vehicle, butnot limited to ethanol, propylene glycol, butanediol, isopropanol,tetrahydrofurfurol (THF), tetrahydrofuran polyethylene glycol ether,glycerol, dimethylacetamide, polyethylene glycol (e.g. polyethyleneglycol 300, polyethylene glycol 400, polyethylene glycol 600), etc.preferably selected from the group consisting of ethanol, propyleneglycol, butanediol, tetrahydrofurfurol, glycerol, polyethylene glycol300, polyethylene glycol 400 and polyethylene glycol 600 and combinationthereof.

In an embodiment of the invention, pharmaceutical compositions maycontain one or more co-solvents, such as benzyl benzoate, polyethyleneglycol (PEG), polypropylene glycol (PPG), propylene glycol (PG),N-methyl-pyrrolidone, dimethyl sulfoxide (DMSO), benzyl alcohol,methanol, ethanol, propanol, glycofurol, sorbitan monolaurate,tetrahydrofuran or dioxane, acetone or mixtures thereof.

In an embodiment of the invention, the ready-to-use or ready-to-dilutecompositions may be formulated as aqueous or non-aqueous solutions.Preferably, the ready-to-use or ready-to-dilute compositions willinclude a vehicle in an amount from about 1 mL to greater than or equalto 100 mL.

According to the present invention, the ready-to-dilute compositions maybe provided in a kit form along with parenterally acceptable diluent.Parenterally acceptable diluents include water for injection, 0.9%saline (normal saline), 0.45% saline (half normal saline) and 2.5%dextrose/0.45% saline.

In certain non-limiting embodiments, meloxicam is formulated as acomposition, wherein meloxicam is the only therapeutically activeingredient present in the composition. In another non-limitingembodiment, meloxicam is formulated as a composition, wherein meloxicamis formulated in combination with at least one or more othertherapeutically active ingredient.

The present application relates to injectable solution of meloxicam,particularly wherein meloxicam is present at a concentration of 5 mg/mLor more. In another aspect, a stable ready-to-use pharmaceuticalcompositions of the present application comprises meloxicam, whereinmeloxicam is present at concentration about 5 mg/mL to about 60 mg/mL,preferably about 30 mg/mL.

Preferably, the stable ready-to-use pharmaceutical compositions forhuman use will be provided as a solution dosage form that is suitablefor intravenous administration. The pharmaceutical compositions may beformulated according to conventional pharmaceutical practice. Thecompositions of the invention can be administered in any conventionalmanner. It will be readily appreciated by those skilled in the art howto administer compositions of the present invention to a human.

In certain aspects, the present application increases solubility ofmeloxicam by one or more of methods selected from (a) particle sizereduction (b) solid dispersion (c) complexation (d) high-speed stirringand e) in situ salt formation.

Salt formation is a popular approach employed to increase the solubilityof poorly soluble drug substances such as meloxicam. Processing a weakacid or base with a counterion can cause in situ salt formation,depending on the properties of the materials. Typically, counterions aresmall inorganic molecules (e.g., sodium, potassium, ammonium,hydrochloride, or phosphate ions) or small organic molecules (e.g.,citrate, tartrate, succinate, mesylate or meglumine) which works bycreating a favourable microenvironment to enhance solubility of thedrug. The water solubility of a counterion can have a directrelationship to an increase in salt solubility.

In an embodiment, stable injectable ready-to-use solutions of meloxicamsuitable for intravenous administration comprises (a) therapeuticallyeffective amount of meloxicam; (b) pharmaceutically acceptable solvent;and (c) optionally, one or more pharmaceutically acceptable excipients.

In an embodiment, stable injectable ready-to-use solutions of meloxicamsuitable for intravenous administration comprises (a) therapeuticallyeffective amount of meloxicam, (b) pharmaceutically acceptable solvent;and (c) one or more pharmaceutically acceptable excipients.

In some embodiments, inventive pharmaceutical composition of theinvention can be formulated for long-term storage of meloxicam at roomtemperature in presence of a suitable pharmaceutically-acceptableexcipient. The pharmaceutically acceptable excipients can increase thehalf-life of meloxicam when stored at any temperature, such as roomtemperature. The presence of the pharmaceutical excipients can decreasethe rate of decomposition of meloxicam at any temperature, such as roomtemperature.

The inventive pharmaceutical compositions of the present inventioncomprise one or more pharmaceutically acceptable liquid excipient(s)selected from, but are not limited to, solvents/co-solvents,surfactants, solubilizers, wetting agents, water immiscible solvents,water, water miscible solvents, hydrophilic solvents, hydrophobicsolvents, preservatives, chelating agents, antioxidants, tonicitycontributing agents, anti-foaming agents, buffering agents, pH adjustingagents, osmotic agents and the like or mixtures thereof.

In an embodiment, solubilizer increases the solubility of meloxicam inpharmaceutical acceptable vehicle. In a pharmaceutical composition, oneor more solubilizers may be included. As used herein, the solubilizermay be selected from the group consisting of meglumine, cyclodextrin,cyclodextrin derivative, monoethanolamine, diethanolamine, tromethamine,hydroxypropyl methyl cellulose (HPMC), L-arginine, L-lysine, polysorbate80 (Tween® 80), polysorbate 20 (Tween® 20), poloxamer, propylene glycol,glycerin, ethanol, polyethylene glycol (300 and 400), sorbitol,dimethylacetamide, and polyethoxylated castor oil (Cremophor® EL) andcombinations thereof. In another embodiment, the pharmaceuticalcompositions of the present invention comprise meloxicam and asolubilizer, wherein the composition further comprises additionalpharmaceutically acceptable excipients.

As stated above, meloxicam is insoluble in nature. The solubilizermeglumine has a rather favourable action to increase the solubility ofmeloxicam. A stable solution of meloxicam can be formulated using asolubilizing amount of meglumine. Meglumine is a carbohydrate derivedfrom sorbitol in which the hydroxyl group in position one is replaced bya methylamine group. The increased applicability of meglumine relates toits ability to form adducts with carboxylic acids and markedly increasestheir solubility in aqueous solutions due to the presence of a largenumber of hydroxyl groups. Because of low toxicity and other favourableproperties, it is suitable even for parenteral applications. A solutioncomposition according to the present invention comprises meloxicam and asolubilizing amount of meglumine. In practice, it is advantageous toprepare a solution of meglumine in water and add meloxicam into suchsolution. Because the solubilization of meglumine is different from thatof ordinary pH adjuster, high-concentration meloxicam solution for humanuse, especially for parenteral administration, can be prepared when itspH value is adjusted back at 6 to 9 with pharmaceutically acceptable pHadjusters after it exceeds 9 during the course of preparation ofmeloxicam solution.

Cyclodextrin or its derivatives also has a favourable action to increasethe solubility of meloxicam. In one embodiment, the cyclodextrin of thepresent invention includes α-cyclodextrin, β-cyclodextrin,δ-cyclodextrin, γ-cyclodextrin, or combinations thereof. In anembodiment, the cyclodextrin of the present application preferablyincludes either a substituted or non-substituted β-cyclodextrin.

Substituted cyclodextrins increase the solubility of the cyclodextrinand mitigate toxic effects associated with unsubstituted cyclodextrins.Examples of substituted β-cyclodextrins include those substituted withone or more hydrophilic groups, such as monosaccharide (e.g., glucosyl,maltosyl), carboxyalkyl (e.g., carboxylmethyl, carboxyethyl),hydroxyalkyl-substituted (e.g., hydroxyethyl, 2-hydroxypropyl) andsulfoalkylether-substituted-β-cyclodextrin.

In one embodiment, the cyclodextrin is a substituted β-cyclodextrin,particularly, hydroxypropyl-β-cyclodextrin (HP-β-CD) andsulfobutylether-β-cyclodextrin (SBE-β-CD). However, it is understoodthat typically any substitution to the cyclodextrin, includingsubstitution by hydrophobic groups such as hydroxyalkylsubstituted-cyclodextrin, will improve its aqueous solubility bydisrupting the hydrogen bonding network within the crystal lattice ofthe solid cyclodextrin, thereby lowering the lattice energy of thesolid. The degree of substitution is not believed to be critical;however, the degree of substitution is advantageously at least 1% andtypically 2% to 10%, such as 3% to 6%.

In a preferred embodiment, the cyclodextrin derivative is a substitutedβ-cyclodextrin, particularly suitable β-cyclodextrins include forexample but not limited to, Cavasol® W7 HP (hydroxypropyl-β-cyclodextrin(HP-β-CD), Kleptose® HP (hydroxypropyl-β-cyclodextrin (HP-β-CD)),Cavamax® W7 (β-cyclodextrin), Captisol®(sulfoalkylether-β-cyclodextrin), Cavasol® W7 M (methyl-β-cyclodextrin),Cavasol® W8 HP (hydroxypropyl-γ-cyclodextrin), Cavamax® W8(γ-cyclodextrin), Cavamax® W6 (α-cyclodextrin). In one aspect, thecyclodextrin is 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), which is acyclic oligosaccharide containing seven D-(+)-glucopyranose units.

In an embodiment, stable injectable ready-to-use solution suitable forintravenous administration comprises (a) meloxicam, (b) water forinjection; (c) meglumine; and (d) optionally, one or more additionalpharmaceutically acceptable excipients.

In an embodiment, stable injectable meloxicam solution suitable forintravenous administration comprises (a) meloxicam, (b) water forinjection; (c) meglumine; and (d) optionally, one or more additionalpharmaceutically acceptable excipients.

In an embodiment, stable injectable meloxicam solution suitable forintravenous administration comprises (a) meloxicam, (b) water forinjection; (c) L-arginine; and (d) optionally, one or more additionalpharmaceutically acceptable excipients.

In an embodiment, stable injectable meloxicam solution suitable forintravenous administration comprises (a) meloxicam, (b) water forinjection; (c) EDTA; and (d) optionally, one or more additionalpharmaceutically acceptable excipients.

In an embodiment, stable injectable meloxicam solution suitable forintravenous administration comprises (a) meloxicam, (b) water forinjection; (c) buffer and e) optionally, one or more additionalpharmaceutically acceptable excipients.

In an embodiment, stable injectable meloxicam solution suitable forintravenous administration comprises (a) meloxicam, (b) water forinjection; (c) Sodium dihydrogen phosphate; (d) disodium hydrogenphosphate, and e) optionally, one or more additional pharmaceuticallyacceptable excipients.

In an embodiment, stable injectable meloxicam solution suitable forintravenous administration comprises (a) meloxicam, (b) water forinjection; (c) TRIS and d) optionally, one or more additionalpharmaceutically acceptable excipients.

In an embodiment, stable injectable meloxicam solution suitable forintravenous administration comprises (a) meloxicam, (b) water forinjection; (c) pH adjusting agent and d) optionally, one or moreadditional pharmaceutically acceptable excipients.

In an embodiment, stable injectable meloxicam solution suitable forintravenous administration comprises (a) meloxicam, (b) water forinjection; (c) hydrochloric acid and d) optionally, one or moreadditional pharmaceutically acceptable excipients.

In an embodiment, stable injectable meloxicam solution suitable forintravenous administration comprises (a) meloxicam; (b) water forinjection; (c) sodium hydroxide and d) optionally, one or moreadditional pharmaceutically acceptable excipients.

In an embodiment, stable injectable meloxicam solution suitable forintravenous administration comprises (a) meloxicam, (b) water forinjection; (c) meglumine; d) EDTA, e) optionally, one or more additionalpharmaceutically acceptable excipients.

In an embodiment, stable injectable meloxicam solution suitable forintravenous administration comprises (a) meloxicam, (b) water forinjection; (c) L-Arginine; d) HP-β-CD, e) optionally, one or moreadditional pharmaceutically acceptable excipients.

In an embodiment, stable injectable meloxicam solution suitable forintravenous administration comprises (a) meloxicam, (b) water forinjection; (c) sodium dihydrogen phosphate monohydrate; d) disodiumhydrogen phosphate anhydrous; e) polyethylene glycol; and f) optionally,one or more additional pharmaceutically acceptable excipients.

In an embodiment, stable injectable ready-to-use solution suitable forintravenous administration comprises (a) meloxicam, (b) water forinjection; (c) hydroxypropyl-β-cyclodextrin (HP-β-CD) and (d)optionally, one or more additional pharmaceutically acceptableexcipients.

In an embodiment, stable injectable ready-to-use solution suitable forintravenous administration comprises (a) meloxicam, (b) water forinjection; (c) meglumine; (d) diethanolamine and (e) optionally, one ormore additional pharmaceutically acceptable excipients.

In an embodiment, stable injectable ready-to-use solution suitable forintravenous administration comprises (a) meloxicam, (b) water forinjection; (c) meglumine; (d) polyethylene glycol and (e) optionally,one or more additional pharmaceutically acceptable excipients.

In an embodiment, stable injectable ready-to-use solution suitable forintravenous administration comprises (a) meloxicam, (b) water forinjection; (c) meglumine; (d) polyethylene glycol; (e) povidone and (f)optionally, one or more additional pharmaceutically acceptableexcipients.

In an embodiment, stable injectable ready-to-use solution forintravenous administration comprises (a) meloxicam, (b) water forinjection; (c) meglumine; (d) hydroxypropyl-β-cyclodextrin (HP-β-CD) and(e) optionally, one or more additional pharmaceutically acceptableexcipients.

In an embodiment, stable injectable ready-to-use solution forintravenous administration comprises (a) meloxicam, (b) water forinjection; (c) meglumine; (d) hydroxypropyl-β-cyclodextrin (HP-β-CD),(e) povidone and (f) optionally, one or more additional pharmaceuticallyacceptable excipients.

In an embodiment, inventive pharmaceutical composition according to theinvention comprises meloxicam, meglumine and one or more additionalsolubilizer, wherein the concentration of solubilizer is from about 2.5mg/mL to about 200 mg/mL.

In an embodiment, inventive pharmaceutical composition according to theinvention comprises meloxicam and meglumine may for example be used in amolar ratio of 0.5:1 to 0.5:10.

In an embodiment, inventive pharmaceutical composition according to theinvention comprises meloxicam and meglumine may for example be used in amolar ratio of 1:0.5 to 10:1.

In an embodiment, inventive pharmaceutical composition according to theinvention comprises meglumine, wherein the meglumine concentration maybe between 10 mg/mL and 50 mg/mL, preferably 15-30 mg/mL, morepreferably 20 mg/mL.

In an embodiment, inventive pharmaceutical composition according to theinvention comprises meloxicam and HP-β-CD may for example be used in amolar ratio of 0.5:1 to 0.5:10.

In an embodiment, inventive pharmaceutical composition according to theinvention comprises meloxicam and polyethylene glycol may for example beused in a molar ratio of 0.5:1 to 0.5:10.

In an embodiment, inventive pharmaceutical composition according to theinvention comprises meloxicam and polyethylene glycol may for example beused in a molar ratio of 1:0.1 to 10:1.

In an embodiment, inventive pharmaceutical composition according to theinvention comprises meloxicam and povidone may for example be used in amolar ratio of 0.5:1 to 0.5:10.

In an embodiment, inventive pharmaceutical composition according to theinvention comprises meloxicam and povidone may for example be used in amolar ratio of 1:0.1 to 10:1.

In another embodiment, inventive pharmaceutical composition according tothe invention comprises meloxicam, meglumine and a cyclodextrinderivative, wherein the concentration of cyclodextrin is from about 5mg/mL to about 200 mg/mL.

The inventive pharmaceutical compositions of the present invention mayadditionally contain suitable pharmaceutically acceptable nucleationinhibitors, but not limited to, polyvinylpyrrolidone (PVP),crospovidone, hydroxypropyl methyl cellulose (HPMC), polysorbate,phospholipids such as dimyristoylphosphatidyl glycerol (DMPG),disteroylphosphatidylethanolamine (DSPE), 1,2-Distearoyl phosphatidylethanolamine methyl-polyethylene glycol conjugate (DSPE-mPEG), or anycombination thereof. In one embodiment, polyvinylpyrrolidone may be PVPK12, PVP K17, PVP K25, PVP K30, PVPK 40 or PVP K90.

The inventive pharmaceutical compositions of the present invention mayadditionally contain a buffering agent, which is used to resist changein pH upon dilution or addition of acid or alkali. Such compoundsinclude, by way of example and without limitation, sodium dihydrogenphosphate monohydrate, disodium hydrogen phosphate anhydrous, aceticacid, sodium acetate, adipic acid, benzoic acid, sodium benzoate, maleicacid, monobasic sodium phosphate, dibasic sodium phosphate, disodiumhydrogen phosphate dodecahydrate, lactic acid, tris buffer, tartaricacid, potassium metaphosphate, potassium phosphate, monobasic sodiumacetate, sodium bicarbonate, sodium tartrate and others known to thoseof ordinary skill in the art.

The inventive pharmaceutical compositions of the present invention mayadditionally contain a “tonicity contributing agent” that can be used toadjust the tonicity of the liquid formulation. Suitable tonicity agentinclude glycerine, lactose, mannitol, dextrose, sodium chloride, sodiumsulphate, sorbitol, trehalose, xylitol, sucrose, maltose and othersknown to those or ordinary skill in the art. In one embodiment, thetonicity of the liquid formulation approximates that of the tonicity ofblood or plasma. The amount of tonicity agent may range from about 1mg/mL to about 20 mg/mL of the composition, preferable from about 5 toabout 10 mg/mL.

The inventive pharmaceutical compositions of the present invention mayadditionally contain a chelating agent selected from the groupconsisting of ethylene-diaminetetraacetic acid (EDTA),diethylenetriaminepentaacetic acid (DTPA), ethylene glycol-bis(β-aminoethyl ether)-tetra acetic acid (EGTA), N-(hydroxyethyl)ethylene-diaminetriacetic acid (HEDTA), nitrilotriacetic acid (NTA),triethanolamine, 8-hydroxyquinoline, tartaric acid, phosphoric acid,gluconic acid, saccharic acid, thiodipropionic acid, acetonicdicarboxylic acid, lecithin, di(hydroxyethyl)glycine, phenylalanine,tryptophan, glycerine, sorbitol and pharmaceutically acceptable saltsthereof. More preferably, the chelating agent is selected from the groupconsisting of EDTA, DTPA, tartaric acid, phosphoric acid, gluconic acidor a pharmaceutically acceptable salt thereof.

The inventive pharmaceutical compositions of the present invention mayadditionally contain an antioxidant which inhibits oxidation and thus isused to prevent the deterioration of preparations by the oxidativeprocess. Such compounds include by way of example and withoutlimitation, acetone, sodium bisulfate, ascorbic acid, ascorbylpalmitate, citric acid, glycine, L-cysteine hydrochloride, L-methionine,butylated hydroxy anisole, butylated hydroxytoluene, hydro phosphorousacid, monothioglycerol, propyl gallate, sodium ascorbate, sodium citrateanhydrous, sodium citrate dihydrate, sodium sulfide, sodium sulfite,sodium bisulfite, sodium formaldehyde sulfoxylate, thioglycolic acid,sodium metabisulfite and others known to those of ordinary skill in theart. The amount of antioxidant may range from about 0.1 mg/mL to about50 mg/mL of the composition, and preferably from about 0.5 mg/mL toabout 25 mg/mL.

The inventive pharmaceutical compositions of the present invention mayadditionally contain a preservative selected from the group consistingof ethanol, benzoic acid and the sodium or potassium salts thereof,sorbic acid and the sodium or potassium salts thereof, chlorobutanol,benzyl alcohol, phenyl ethanol, methyl, ethyl, propyl orbutyl-p-hydroxybenzoates, phenol, m-cresol, p-chloro-m-cresol,phenylmercury nitrate or benzalkonium chloride.

The inventive pharmaceutical compositions of the present invention mayadditionally contain pH adjusting agents. The pH adjusting agents areselected from the group consisting of sodium hydroxide, potassiumhydroxide, magnesium hydroxide, sodium carbonate, tromethamine, sodiumlinoleate, sodium oleate, potassium carbonate, potassium linoleate,potassium oleate, and mixtures thereof. In one embodiment,pharmaceutical composition comprising meloxicam can be formulated at anysuitable pH. The pH of the pharmaceutical composition preferably rangesfrom about 5 to about 10, preferably from about 7 to about 9, mostpreferably about 8 when measured at room temperature. In one embodiment,pharmaceutical composition comprising meloxicam can be formulated byusing any suitable pH adjusting agent. In a preferred aspect, it ispossible to maintain the pH of the said composition without using asuitable buffering agent.

The inventive pharmaceutical compositions of the present invention mayadditionally contain anti-foaming agents. The anti-foaming agents areselected from the group consisting of Sodium carboxymethylcellulose,sorbitol, mannitol, polyvinylpyrrolidone (PVP), Polyoxyethylene sorbitanmonolaurate or monooleate, polysorbates or Tween 20 and 80,polyoxyethylene/ polyoxypropylene/polyoxyethylene copolymer (PluronicL-62), glycerol polyethylene glycol ricinoleate (Cremophor EL), siliconeantifoam (Dimeticone), sorbitan monooleate or monolaurate (Span 20 and80), propylene glycol; polyethylene glycol 300 (PEG), ethanol, dimethylacetamide (DMA), glycerol, N-methyl-2-pyrrolidone, and monothioglycerol.

In another embodiment, the stable aqueous parenteral solution comprisingmeloxicam has a viscosity value between of about 1 cP (centipoise) and 5cP, for example, 1.5 cP, 2 cP, 2.5 cP, 3 cP, 3.5 cP, 4 cP or 4.5 cP.

In another embodiment, the stable aqueous parenteral solutioncomprising, meloxicam has an osmolality value of between about 100 mOsmand about 2000 mOsm, for example, about 100 mOsm, about 150 mOsm, about200 mOsm, about 250 mOsm, about 300 mOsm, about 350 mOsm, about 400mOsm, about 450 mOsm, about 500 mOsm, about 550 mOsm, about 600 mOsm,about 650 mOsm, about 700 mOsm, about 750 mOsm, about 800 mOsm, about850 mOsm, about 900 mOsm, about 950 mOsm, about 1000 mOsm, about 1100mOsm, about 1150 mOsm, about 1200 mOsm, about 1250 mOsm, about 1300mOsm, about 1350 mOsm, about 1400 mOsm, about 1450 mOsm, about 1500mOsm, about 1550 mOsm, about 1600 mOsm, about 1650 mOsm, about 1700mOsm, about 1750 mOsm, about 1800 mOsm, about 1850 mOsm, about 1900mOsm, about 1950 mOsm, about 2000 mOsm.

In yet another embodiment, the present invention relates to method ofreducing moderate to severe post-operative pain as well as opioidrequirements in a human subject, the method comprising administering thehuman subject a solution comprising meloxicam, wherein the compositionexhibits rapid onset of action and provides faster relief of pain.

In yet another embodiment, the present invention relates to treatment ofosteoarthritis and rheumatoid arthritis in a human subject, the methodcomprising administering the human subject a solution comprisingmeloxicam, wherein the composition exhibits rapid onset of action andprovides faster relief of pain.

According to a preferred embodiment, the present invention relates topharmaceutical compositions useful for treating moderate to moderatelysevere acute pain and/or prescribed for the management of severe pain asan adjunct therapy to opioid analgesics and may allow a reduction in theopioid dose and corresponding adverse events associated with opioid use.When the meloxicam composition of the present invention is formulatedinto an injectable dosage form and administered to a patient in needthereof, the composition provides a time to first perceptible painrelief. Time to first perceptible pain relief is the time fromadministration of the drug to the point at which subject first perceivesa change in their pain intensity. The time to perceptible pain reliefranges from about less than 1 minute, from about 1 to 30, 2 to 25, 5 to20, 10 to 20 and 12 to 18 minutes. In other words, an injectable form ofthe present invention, when administered to a patient in need thereof,provides a time to first perceptible pain relief in about 30, 25, 20,18, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or less than 1minute.

According to another embodiment, when the stable injectable solution ofmeloxicam of the present invention is formulated into an injectabledosage form and administered to a subject in need thereof, thecomposition of the invention provides a time to meaningful pain relief.Time to meaningful pain relief is the time from administration of thedrug to the point at which the patient first perceives a meaningfulreduction in pain intensity. The time to first meaningful pain reliefranges from about less than 25, from 25 to 300, 75 to 250, 100 to 200,and 115 to 125 minutes. In other words, an injectable form of thepresent invention, when administered to a patient in need thereof,provides a time to meaningful pain relief in about 300, 275, 250, 225,200, 195, 185, 175, 165, 155, 150, 125, 100, 75, 50, 25, or less than 25minutes.

According to yet another embodiment, when the meloxicam solution isformulated into an injectable dosage form and administered to a subjectin need thereof, the composition of the invention provides meaningfulpain relief for an extended period of time, such as, a period of up to24 hours. According to other exemplary embodiments, the expended periodof time that patients experience meaningful pain relief ranges fromabout 120 to 1440, 180 to 1320, 240 to 1260, 300 to 1200, 360 to 1140,480 to 1080, 540 to 1020, 600 to 960, 660 to 900, or 720 to 840 minutes.In other words, an injectable form, of the present invention, whenadministered to a patient in need thereof, provides a meaningful painrelief for up to about 120, 180, 240, 300, 360, 420, 480, 540, 600, 660,720, 780, 840, 900, 960, 1020, 1080, 1140, 1200, 1260, 1320, or 1440minutes. In a preferred embodiment, an exemplary method for treatingmoderate to moderately severe acute pain comprises administering to apatient in need thereof, an intravenous dosage form comprising 15 mg, 30mg, or 60 mg, of meloxicam which provides a duration of analgesic effectfor up to 1440 minutes (i.e., 24 hours).

According to yet another embodiment, the stable injectable solution ofmeloxicam suitable for parenteral administration comprising (a)therapeutically effective amount of meloxicam, (b) pharmaceuticallyacceptable solvent; (c) one or more solubilizers; and (d) optionally,one or more other pharmaceutically acceptable excipients, whereinsubject administered with the said composition has shown increasedaverage paw withdrawal latency by 68% when compared with subjectadministered with reference composition has showed 49% of increasedaverage paw withdrawal latency.

According to yet another embodiment, the present invention providesstable injectable meloxicam solutions at concentrations higher than 5mg/mL and methods of preparing such solutions. In particular, thepresent invention provides stable aqueous meloxicam solutions forparenteral administration at concentrations about 5 mg/mL, about 6mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, about 10 mg/mL,about 11 mg/mL, about 12 mg/mL, about 13 mg/mL, about 14 mg/mL, about 15mg/mL, about 16 mg/mL, about 17 mg/mL, about 18 mg/mL, about 19 mg/mL,about 20 mg/mL, about 21 mg/mL, about 22 mg/mL, about 23 mg/mL, about 24mg/mL, about 25 mg/mL, about 26 mg/mL, about 27 mg/mL, about 28 mg/mL,about 29 mg/mL and about 30 mg/m L.

Further in other embodiments, the present invention provides stableinjectable meloxicam solutions at concentrations higher than 5 mg/mL andmethods of preparing such solutions. In particular, the presentinvention provides stable aqueous meloxicam solutions for parenteraladministration at concentrations about 5 mg/mL, about 5.5 mg/mL, about 6mg/mL, about 6.5 mg/mL, about 7 mg/mL, about 7.5 mg/mL, about 8 mg/mL,about 8.5 mg/mL, about 9 mg/mL, about 9.5 mg/mL, about 10 mg/mL, about10.5 mg/mL, about 11 mg/mL, about 11.5 mg/mL, about 12 mg/mL, about 12.5mg/mL, about 13 mg/mL, about 13.5 mg/mL, about 14 mg/mL, about 14.5mg/mL, about 15 mg/mL, about 15.5 mg/mL, about 16 mg/mL, about 16.5mg/mL, about 17 mg/mL, about 17.5 mg/mL, about 18 mg/mL, about 18.5mg/mL, about 19 mg/mL, about 19.5 mg/mL, about 20 mg/mL, about 20.5mg/mL, about 21 mg/mL, about 21.5 mg/mL, about 22 mg/mL, about 22.5mg/mL, about 23 mg/mL, about 23.5 mg/mL, about 24 mg/mL, about 24.5mg/mL, about 25 mg/mL, about 25.5 mg/mL, about 26 mg/mL, about 26.5mg/mL, about 27 mg/mL, about 27.5 mg/mL, about 28 mg/mL about 28.5mg/mL, about 29 mg/mL, about 29.5 mg/mL and about 30 mg/mL.

The unit dose of the meloxicam will be in the range from about 1 toabout 200 mg. Exemplary unit dose of meloxicam range from 5 mg to 200mg, including unit dosages of 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 40 mg, 42.5mg, 45 mg, 50 mg, 52.5 mg, 55 mg, 57.5 mg, 60 mg, 62.5 mg, 65 mg, 70 mg,72.5 mg, 75 mg, 80 mg, 82.5 mg, 85 mg, 87.5 mg, 90 mg, 92.5 mg, 95 mg,97.5 mg, 100 mg, 102.5 mg, 105 mg, 107.5 mg, 110 mg, 112.5 mg, 115 mg,117.5 mg, 120 mg, 122.5 mg, 125 mg, 127.5 mg, 130 mg, 132.5 mg, 135 mg,140 mg, 142.5 mg, 145 mg, 150 mg, 152.5 mg, 155 mg, 157.5 mg, 160 mg,162.5 mg, 165 mg, 170 mg, 172.5 mg, 175 mg, 180 mg, 182.5 mg, 185 mg,187.5 mg, 190 mg, 192.5 mg, 195 mg, 197.5 mg and 200 mg, wherein unitdose may be packed in vial, ampoule, pre-filled syringe, cartridge orauto-injector.

In certain embodiment, the stable injectable meloxicam solutioncomprising therapeutically effective amount of meloxicam of theinvention may provide value of T_(max) less than 5 hours, for example,less than 4 hours, less than 3 hours, less than 2 hours, less than 1hour, less than 45 minutes, less than 30 minutes, less than 20 minutes,less than 10 minutes, less than 5 minutes, less than 3 minutes or lessthan 1 minute or less than 30 seconds, when the solution is administeredvia subcutaneous or intramuscular route to a human at a meloxicam dosebetween of 7.5 mg and 60 mg. The solution comprising therapeuticallyeffective amount of meloxicam of the invention provides immediateavailability of the entire dose of meloxicam in the blood when thesolution is administered via intravenous route to a human.

In further embodiment, the stable injectable meloxicam solutioncomprising meloxicam of the invention may provide value of C_(max) morethan 0.5 μg/mL, for example, more than 0.5 μg/mL, more than 1 μg/mL,more than 1.5 μg/mL, more than 2 μg/mL, more than 2.5 μg/mL, more than 3μg/mL, more than 3.5 μg/mL, more than 4 μg/mL, more than 4.5 μg/mL, morethan 5 μg/mL, more than 5.5 μg/mL, more than 6 μg/mL, more than 6.5μg/mL, more than 7 μg/mL, more than 7.5 μg/mL, more than 8 μg/mL, morethan 8.5 μg/mL, more than 9 μg/mL, more than 9.5 μg/mL, more than 10μg/mL, more than 15 μg/mL, more than 20 μg/mL, more than 25 μg/mL, morethan 30 μg/mL, more than 35 μg/mL, more than 40 μg/mL, more than 45μg/mL, more than 50 μg/mL, more than 55 μg/mL, more than 60 μg/mL, morethan 65 μg/mL, more than 70 μg/mL, more than 75 μg/mL, more than 80μg/mL, more than 85 μg/mL, more than 90 μg/mL, more than 95 μg/mL, ormore than 100 μg/mL, when the solution administered via parenteral routeto a subject at a meloxicam dose of between 7.5 mg and 60 mg.

In further embodiment, the stable injectable meloxicam solutioncomprising meloxicam of the invention may provide value of AUC more than10 μg*h/mL, more than 20 μg*h/mL, more than 30 μg*h/mL, more than 40μg*h/mL, more than 50 μg*h/mL, more than 60 μg*h/mL, more than 70μg*h/mL, more than 80 μg*h/mL, more than 90 μg*h/mL, more than 100μg*h/mL, more than 150 μg*h/mL, more than 200 μg*h/mL, more than 250μg*h/mL, more than 300 μg*h/mL, more than 350 μg*h/mL, more than 400μg*h/mL, more than 450 μg*h/mL, more than 500 μg*h/mL, more than 550μg*h/mL, more than 600 μg*h/mL, more than 650 μg*h/mL, more than 700μg*h/mL, more than 750 μg*h/mL, more than 800 μg*h/mL, more than 850μg*h/mL, more than 900 μg*h/mL, more than 950 μg*h/mL, more than 1000μg*h/mL, more than 1050 μg*h/mL, more than 1100 μg*h/mL, more than 1150μg*h/mL, more than 2000 μg*h/mL when the solution is administered viaparenteral route to a subject at a meloxicam dose of between 7.5 mg and60 mg.

In certain embodiments, the stable injectable meloxicam solutionsuitable for parenteral administration comprises (a) therapeuticallyeffective amount of meloxicam, (b) pharmaceutically acceptable solvent;(c) one or more solubilizers; and (d) optionally, one or more otherpharmaceutically acceptable excipients, wherein in said composition uponparenteral administration exhibits bioequivalence to a commerciallyavailable reference meloxicam drug product (such as Anjeso®), andwherein said bioequivalence is established by at least one of: (i) aconfidence interval for mean AUC_(0-t) between about 80% and about 125%;(ii) a confidence interval for mean AUC_(0-infinity) between about 80%and about 125%; (iii) a confidence interval for mean C_(max) betweenabout 80% and about 125% or combinations thereof.

In certain embodiments, the stable injectable meloxicam solutionsuitable for intravenous administration comprises (a) therapeuticallyeffective amount of meloxicam, (b) pharmaceutically acceptable solvent;(c) one or more solubilizers; and (d) optionally, one or more otherpharmaceutically acceptable excipients, wherein in said composition uponparenteral administration exhibits bioequivalence to a commerciallyavailable reference meloxicam drug product (such as Anjeso®), andwherein said bioequivalence is established by at least one of: (i) aconfidence interval for mean AUC_(0-t) between about 80% and about 125%;(ii) a confidence interval for mean AUC_(0-infinity) between about 80%and about 125%; (iii) a confidence interval for mean C_(max) betweenabout 80% and about 125%; or combinations thereof.

In certain embodiments, the stable injectable meloxicam solutionsuitable for parenteral administration comprises (a) therapeuticallyeffective amount of meloxicam, (b) pharmaceutically acceptable solvent;(c) one or more solubilizers; (d) one or more nucleation inhibitor; and(e) optionally, one or more other pharmaceutically acceptableexcipients, wherein in said composition upon parenteral administrationexhibits bioequivalence to a commercially available reference meloxicamdrug product (such as Anjeso®), and wherein said bioequivalence isestablished by at least one of: (i) a confidence interval for meanAUC_(0-t) between about 80% and about 125%; (ii) a confidence intervalfor mean AUC_(0-infinity) between about 80% and about 125%; (iii) aconfidence interval for mean C_(max) between about 80% and about 125% orcombinations thereof.

In certain embodiments, the stable injectable meloxicam solutionsuitable for intravenous administration comprises (a) therapeuticallyeffective amount of meloxicam, (b) pharmaceutically acceptable solvent;(c) one or more solubilizers; (d) one or more nucleation inhibitor; and(e) optionally, one or more other pharmaceutically acceptableexcipients, wherein in said composition upon parenteral administrationexhibits bioequivalence to a commercially available reference meloxicamdrug product (such as Anjeso®), and wherein said bioequivalence isestablished by at least one of: (i) a confidence interval for meanAUC_(0-t) between about 80% and about 125%; (ii) a confidence intervalfor mean AUC_(0-infinity) between about 80% and about 125%; (iii) aconfidence interval for mean C_(max) between about 80% and about 125%;or combinations thereof.

In further embodiments, the stable injectable meloxicam solutionsuitable for intravenous administration comprises (a) therapeuticallyeffective amount of meloxicam, (b) pharmaceutically acceptable solvents;(c) one or more solubilizers; and (d) one or more nucleation inhibitorse) optionally, one or more other pharmaceutically acceptable excipients,wherein in said composition upon parenteral administration exhibitsbioequivalence to a commercially available reference meloxicam drugproduct (such as Anjeso®), and wherein said bioequivalence isestablished by at least one of: (i) a confidence interval for meanAUC_(0-t) between about 80% and about 125%; (ii) a confidence intervalfor mean AUC_(0-infinity) between about 80% and about 125%.

In certain embodiments, the invention relates to methods for making acomposition, which comprise: (i) dispensing required quantity water forinjection; (ii) adding one or more solubilizing agents to form a firstsolution; (iii) adding meloxicam to the first solution to form a secondsolution; and (iv) optionally, adjusting the pH of the second solutionby adding a suitable acid or base, e.g., hydrochloric acid and/or sodiumhydroxide final volume was made with water for injection.

In certain embodiments, the invention relates to methods for making acomposition, which comprise: (i) dispensing required quantity water forinjection; (ii) adding one or more solubilizing agents to form a firstsolution; (iii) adding meloxicam to the first solution to form a secondsolution; (iv) adding one or more solvents and (v) optionally, adjustingthe pH of the second solution by adding a suitable acid or base, e.g.,hydrochloric acid and/or sodium hydroxide (vi) final volume was madewith water for injection.

In certain embodiments, the invention relates to methods for making acomposition, which comprise: (i) dispensing required quantity water forinjection; (ii) adding one or more solubilizing agents to form a firstsolution; (iii) adding meloxicam to the first solution to form a secondsolution; (iv) adding one or more nucleation inhibitor (v) adding one ormore solvents and (vi) optionally, adjusting the pH of the secondsolution by adding a suitable acid or base, e.g., hydrochloric acidand/or sodium hydroxide (vii) final volume was made with water forinjection.

Certain embodiments additionally relate to sterilizing the finishedproducts, e.g., aseptic filtration-filling-sealing, terminalsterilization, incorporation of sterilizing agents, irradiation, and/orheating.

Sterilization may be accomplished by any of the conventional methodsincluding aseptic filling, irradiation and heat sterilization. Heatsterilization is normally performed using steam, preferably wet steam toallow for the use of pressure as a means of temperature control. Thetime period for the sterilization must be long enough to meet thesterility requirements required of an injectable product. When steam isused, the period may be from about 5 to 30 minutes at temperatures ofabout 110° C. to 130° C., or from about 10 to 30 minutes at temperaturesof about 110° C. to 130° C., preferably at 120° C. to 125° C. for 15 to30 minutes. In another embodiment, the sterilization can be at 120° C.for 5 to 15 minutes.

A pharmaceutically inert gas may be bubbled into the solution to driveout oxygen, which may be selected from nitrogen or carbon dioxide.Preferably, the solution was kept under nitrogen or carbon dioxidesparging until dissolved oxygen less than 10 mg/L in the final solution.

Containers suitable according to the present invention are those knownin the art. They include vials, cartridges, pre-filled syringes,auto-injectors, infusion bags, bottles and ampoule presentations.Containers may be fabricated from glass or from polymeric materials.Suitable containers should be of a size sufficient to hold one or moredoses of meloxicam.

The present invention provides for stable injectable meloxicam solutionin single-dose and/or multi-dose compositions. In some embodiments, thecomposition may be contained in vials. In some embodiments, the vialsmay be made from clear glass, amber glass, or plastic. In someembodiments, the vials or pre-filled syringes may be in the range ofabout 0.1 mL to 100 mL in volume, preferably in the range of about 1 mLto 50 mL, more preferably in the range of about 1 mL to 10 mL, and mostpreferably in the range of about 1 mL to 5 mL. In some embodiments, thecomposition may exist in a 5 mL vial. In some embodiments, the 5 mL vialmay be a single-dose formulation. In some embodiments, the 10 mL vialmay be a multi-dose formulation. In some embodiments, the same vial maybe used for multiple applications of the composition for up to about 10days after initial use, preferably up to about 15 days, more preferablyup to about 30 days, more preferably up to about 45 days, and mostpreferably up to about 60 days.

In another embodiment the vial, ampoule or syringe is dimensioned so asto have a nominal maximum fill volume of between about 1 mL and about 10mL. In certain embodiments the nominal maximum fill volume is betweenabout 1 mL and about 5 mL. In certain embodiments the nominal maximumfill volume is about 1 mL or about 2 mL.

The polymeric materials which may be used include: polysulfone,polycarbonate, polypropylene, polyethylene (LDPE or HDPE),ethylene/propylene copolymers, polyolefins, acrylic-imide copolymers,polyester (e.g. PET, PEN and the like), Teflon, Nylon, acetal (Delrin),polymethylpentene, PVDC, ethylvinylacetate, AN-copolymer etc. Inaddition, crystal zenith (CZ) resin containers and similar resins can beused as rigid containers and syringes.

A ready-to-use pre-filled syringe comprising stable injectable meloxicamsolution according to the invention will be advantageous, as compared tovials or ampoules. A pre-filled syringe fabricated from a polymer willnot only be convenient for handling, storage and administration, butwill also minimize mixing or dosing errors. The pre-filled syringeaccording to the invention may also include single use auto injectorsand reusable auto injectors. The pre-filled syringe contains variousconstituent parts, for example, a sterile dear USP Type-I siliconizedglass syringe barrel (1 mL, cut flange with a gauge (29 size),hypodermic needle (½ inch) fitted with rigid needle shield and laminatedbromobutyl plunger stopper for the barrel.

In another embodiment, the present invention provides a kit comprisingan auto injector which contains a pre-filled syringe (a pre-filledsyringe assembled /placed in the auto injector). The autoinjector may beintegrated with a needle stick protection feature and holds a pre-filledsyringe containing a single dose, whereby the entire deliverable volumeis expelled.

The stable injectable meloxicam solution preparations as describedherein may further comprise effective amounts of one or more othertherapeutically active ingredient. Suitable other active ingredientsused in some of the embodiments of present disclosure include, but arenot limited to, Nonsteroidal anti-inflammatory drugs (NSAIDs), opioids,corticosteroids, anaesthetic agents or mixtures thereof.

Stability: As used herein, the term “stable” is defined as no more thanabout 5% loss of meloxicam under typical commercial storage conditions.In certain embodiments, the compositions of the present invention willhave no more than about 2% loss of meloxicam, more preferably, no morethan about 1% loss of meloxicam, under typical commercial storageconditions. The composition retains at least about 95% of the potency ofmeloxicam after storing the composition at 40° C. and 75% relativehumidity (herein after mentioned as RH) for at least three months. Incertain aspects, the term “stable” refers to chemical stability, whereinnot more than 1.5% w/w of total related substances are formed on storageat accelerated conditions of stability at 40° C. and 75% RH or at 25° C.and 60% RH or 2-8° C. for a period of at least six months or to theextent necessary for use of the composition.

In another embodiment, the stable injectable meloxicam solutioncomprising meloxicam, may have a shelf life after opening of 14 days ormore.

In certain embodiments, the inventive pharmaceutical compositionsaccording to the invention is stable for at least 3 months at 25° C. and60% RH. In certain embodiments, the composition according to theinvention is stable for at least 3 months at 40° C. and 75% RH. Incertain embodiments, the composition according to the invention isstable for at least 24 months when stored under room temperature.

In particular, the Impurity-B (i.e., 2-Amino-5-methylthiazole), formeddue to hydrolytic degradation, may be monitored. The structure ofmeloxicam impurity-B is shown below:

In certain embodiments, the inventive pharmaceutical compositionaccording to the invention has a level of Impurity-B that is less than2% as measured by HPLC, preferably less than 1% as measured by HPLC, andmost preferably less than 0.5% as measured by HPLC.

In particular, the oxalate impurity (i.e.,4-Hydroxy-2-(methyl-thio)-pyrimidine-5-carboxylic acid) formed due tooxidative degradation, may be monitored. The structure of oxalateimpurity is shown below:

In certain embodiments, the inventive pharmaceutical compositionaccording to the invention has a level of oxalate impurity that is lessthan 2% as measured by HPLC, preferably less than 1% as measured byHPLC, and most preferably less than 0.5% as measured by HPLC.

In an embodiment, inventive pharmaceutical compositions of the presentapplication were found to remain in solution, without anyrecrystallization or precipitation, when stored for 6 months at 2-8° C.,25° C./60% RH condition or 40° C./75% RH conditions.

In an embodiment, the invention relates to stable injectable meloxicamsolution intended for intravenous administration comprising aboutmeloxicam and solubilizers, wherein the solution is stable for at least6 months at 40° C./75% RH condition.

In another embodiment, the invention relates to stable injectablemeloxicam solution comprising meloxicam, wherein the solution is stablefor at least 3 months at 2° C. to 8° C.

In another embodiment, the stable injectable meloxicam solutioncomprising meloxicam is dear (free of any crystals/precipitates) byvisual, inspection after storage for at least 1 month, for example, 2months, 3 months, 6 months, 12 months, 18 months, or 24 months, atcontrolled room temperature. The solution of the present inventionprovides value of absorbance not more than 1, for example, not more then0.75, 0.5, 0.4, 0.3, 0.2, 0.1 or 0.05 and value of % transmittance notless than 90%, for example, not less than 95%, 96%, 97%, 98%, 99%, 99.5%or 99.9

In another embodiment, the stable injectable meloxicam solutioncomprising meloxicam does not contain4-Hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid ethyl ester1,1-dioxide (also known as Impurity-A) more than 0.5%, for example,0.4%, 0.3%, 0.2%, 0.1% or 0.05%, by weight of meloxicam, as measured byHPLC.

In another embodiment, the stable injectable meloxicam solutioncomprising meloxicam does not contain 2-amino-5-methyl-thiazole (alsoknown as Impurity-B) more than 0.5%, for example, 0.4%, 0.3%, 0.2%, 0.1%or 0.05%, by weight of meloxicam, as measured by HPLC.

In another embodiment, the stable injectable meloxicam solutioncomprising meloxicam does not containMethyl-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-Dioxide(also known as Impurity-D) more than 0.5%, for example, 0.4%, 0.3%,0.2%,0.1% or 0.05%, by weight of meloxicam, as measured by HPLC.

In another embodiment, the stable injectable meloxicam solutioncomprising meloxicam does not containN-(3,5-dimethylthiazol-2-(3H)-ylidene)-4-hydroxy-2-methyl-2H-benzo[e][1,2]thiazine-3-carboxamide-1,1-dioxide(also known as Impurity E) more than 0.5%, for example, 0.4%, 0.3%,0.2%, 0.1% or 0.05%, by weight of meloxicam, as measured by HPLC.

In another embodiment, the stable injectable meloxicam solutioncomprising meloxicam does not containN-(3-Ethyl-5-methylthiazol-2(3H)-ylidene)-4-hydroxy-2-methyl-2H-benzo[e][1,2]thiazine-3-carboxamide-1-dioxide(Ethyl meloxicam impurity) more than 0.5%, for example, 0.4%, 0.3%,0.2%, 0.1% or 0.05%, by weight of meloxicam, as measured by HPLC.

In another embodiment, the stable injectable meloxicam solutioncomprising meloxicam does not contain2-(diazinyl-sulfonyl)-N-methylaniline-oxide (Meloxicam diazinyl-sulfonylImpurity) more than 1%, for example, 0.8%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%or 0.055% by weight of meloxicam, as measured by HPLC.

In another embodiment of the invention, there is provided stableinjectable meloxicam solution comprising meloxicam, wherein the solutiondoes not contain single maximum unknown impurity more than 1% and/ordoes not contain total impurities more than 3% (for example, not morethan 2%, 1%, or 0.5%) after storage for more than 2 months, for example,for 3 months, for 6 months, for 12 months, for 18 months, for 24 monthsor for 36 months when stored at (i) 2-8° C. temperature or at (ii) 25±2°C. temperature and 60±5% RH or at (iii) 40±2° C. and 75±5% RH. Theparenteral solution comprising meloxicam of the present invention doesnot form any precipitate and remains physically stable after storage formore than 2 months, for example, for 3 months, for 6 months, for 12months, for 18 months, for 24 months or for 36 months when stored at2-8° C. temperature or at 25±2° C. temperature and 60±5% RH.

In another embodiment, the stable injectable meloxicam solutioncomprising meloxicam has a shelf-life in the sealed original packagingmay be 1 month or more, in particular between 1 month and 36 months, butat least between 1 month and 24 months, preferably between 1 month and12 months.

Dosage and Administration: The inventive pharmaceutical compositions asdescribed herein may be used in treating moderate-to-severe pain inwhich therapeutically effective amount of meloxicam is administered to ahuman subject.

For administration to human subjects, the inventive pharmaceuticalcompositions comprise an effective dosage amount of meloxicam. Theformulation may be prepared using conventional methods, for example,depending on the subject to be treated, the mode of administration, andthe type of treatment desired (e.g., prevention, prophylaxis, ortherapy).

Preferably, the present application relates to method for managing ortreating or alleviating moderate-to-severe pain, alone or in combinationwith non-NSAID analgesics, the method comprising administering the humansubject, a pharmaceutical composition comprising meloxicam.

More preferably, the present application relates to method for managingor treating or alleviating moderate-to-severe pain alone or incombination with non-NSAID analgesics not limiting to opioids or localanaesthetics, the method comprising administering the human subject, apharmaceutical composition comprising meloxicam.

In another aspect, the present invention relates to method for managingor treating or alleviating the signs and symptoms of osteoarthritis,rheumatoid arthritis and pauciarticular or polyarticular course juvenilerheumatoid arthritis (JRA)/juvenile idiopathic arthritis (JIA) in thehuman subject, wherein the method comprises administering the humansubject, a pharmaceutical composition comprising meloxicam.

Determination of meloxicam optimal dosage may require individualtitration. Therapy may be started at a low dosage, and increasegradually until optimum effect is achieved (e.g., usually between 5-40mg daily). In certain embodiments, 1-20 mL of meloxicam solution may beadministered intravenously to achieve optimum effect, preferably 1-10 mLmay be administered to achieve optimum effect.

In an embodiment, the present invention relates to preventing ormanaging or treating or alleviating moderate-to-severe pain or mild tosevere pain or post-surgical pain in a human subject, the methodcomprising administering 30 mg of meloxicam solution once daily, asintravenous bolus injection over 15 seconds to a human subject.

In one embodiment of the method as disclosed herein, the intravenousdose (including a bolus dose) of meloxicam is administered to thepatient over the course of about 1 to about 60 seconds, including allvalues and sub-ranges there between. The IV dose of meloxicam may beadministered to patient in about 1 second, about 2 seconds, about 3seconds, about 4 seconds, about 5 seconds, about 6 seconds, about 7seconds, about 8 seconds, about 9 seconds, about 10 seconds, about 11seconds, about 12 seconds, about 13 seconds, about 14 seconds, about 15seconds, about 16 seconds, about 17 seconds, about 18 seconds, about 19second, about 20 seconds, about 21 second, about 22 seconds, about 23seconds, about 24 seconds, about 25 second, about 26 seconds, about 27seconds, about 28 seconds, about 29 second, about 30 seconds, about 31second, about 32 seconds, about 33 seconds, about 34 seconds, about 35second, about 36 seconds, about 37 seconds, about 38 seconds, about 39second, about 40 seconds, about 41 second, about 42 seconds, about 43seconds, about 44 seconds, about 45 second, about 46 seconds, about 47seconds, about 48 seconds, about 49 second, about 50 seconds, about 51second, about 52 seconds, about 53 seconds, about 54 seconds, about 55second, about 56 seconds, about 57 seconds, about 58 seconds, about 59second, or about 60 seconds, or any ranges between these values.

For example, in some embodiments, the IV dose (including a bolus dose)of meloxicam is administered to the patient over the course of about 5to about 45 seconds. In other embodiments, the IV dose of meloxicam isadministered to the patient over the course of about 10 to about 40seconds. In still other embodiments, the IV dose of meloxicam isadministered to the patient over the course of about 15 to about 35seconds. In some embodiments, the IV dose of meloxicam is administeredto the patient over the course of about 10 to about 30 seconds. Incertain embodiments, the IV dose of meloxicam is administered to thepatient over the course of about 15 to about 30 seconds. In oneembodiment, the IV dose of meloxicam is administered to the patient overabout 15 seconds.

In one embodiment, the dose of meloxicam is in the range of from about 5mg to about 200 mg. In some embodiments, the dose of meloxicam is in therange of from about 15 mg to about 180 mg. In some embodiments, the doseof meloxicam is in the range of from about 15 mg to about 100 mg. Inother embodiments, the dose of meloxicam is in the range of from about15 mg to about 80 mg. In some embodiments, the dose of meloxicam is inthe range of from about 20 mg to about 70 mg. In some embodiments, thedose of meloxicam is in the range of from about 30 mg to about 60 mg. Insome embodiments, the dose of meloxicam is about 30 mg. In anotherembodiment, the dose of meloxicam is about 60 mg.

In some embodiments, the methods comprise administering stableinjectable meloxicam solution to a subject at about 12 hours, at about18 hours, at about 24 hours, at about 36 hours, at about 48 hours, atabout 54 hours, at about 72 hours, at about 96 hours, at about 5 days,at about 6 days, and so forth subsequent to the first dose of meloxicamadministered to the subject.

In one embodiment, the methods disclosed herein comprise administeringto the patient a dose of meloxicam intravenously, wherein the meloxicamis at a dose of about 30 mg. In some embodiments, the methods disclosedherein comprise administering to the patient a dose of meloxicamintravenously, wherein the meloxicam is at a concentration of about 7.5mg/mL or 30 mg/mL. In one embodiment, the intravenous dose is a bolusdose.

In one embodiment of the method as disclosed herein, the dose ofmeloxicam is administered after the patient has undergone a surgicalprocedure. In one embodiment, the surgical procedure is an open surgicalprocedure. In another embodiment, the surgical procedure is alaparoscopic surgical procedure. In other embodiments, the surgicalprocedure was performed on hard tissue. In some embodiments, thesurgical procedure was performed on soft tissue.

In an embodiment, the present invention relates to method of treatingsigns and symptoms of polyarticular course juvenile rheumatoid arthritis(JRA)/juvenile idiopathic arthritis (JIA) in patients of age less than18 years with a dose of meloxicam ranging from 0.1 mg/kg a day to 0.2mg/kg a day.

In certain aspects, the inventive pharmaceutical compositions describedherein may be used to treat adults and adolescents (e.g., about 13-17years). In certain aspects, the pharmaceutical compositions describedherein may be used as monotherapy or as adjunctive therapy. For example,additional active agents may be used in adjunctive therapy withmeloxicam, such as opioid medications (e.g., morphine, hydromorphone,etc.).

The dosage levels can be dependent on the nature of the condition, drugefficacy, the condition of the patient, the judgment of thepractitioner, and the frequency and mode of administration. The unitdosage forms can be administered to achieve any daily amount describedherein, such as by administering one to five times daily (e.g., one,two, three, four, or five times daily).

The inventive pharmaceutical compositions of the present disclosureprovide for a non-oral, easy-to-administer option for patients havingmoderate-to-severe pain.

General HPLC procedure: As explained in detail below, the following HPLCprocedure can be used to detect and quantify impurities of meloxicam Thematerials and general conditions are listed below:

TABLE 1 Related substances identification by HPLC Chromatographicconditions Instrument HPLC with Dual wavelength detector Column InertSustain C18, 250 mm × 4.6 mm, 3μ (Cat. No.: 5020-07446) Pump modeGradient Flow rate 0.8 mL/minute Detector wavelength 260 nm and 350 nmwith dual wavelength detector Column oven 40° C. temperature Samplecooler 25° C. temperature Injection volume 10 μL Run time 60 minutesPreparation of Mobile Prepare a mixture of Buffer* and organic phase-Amodifier* in the ratio of 70:30 (% v/v) and degas for about 10 minutes.Preparation of Mobile Prepare a mixture of Buffer and organic phase-Bmodifier in the ratio of 30:70 (% v/v) and degas for about 10 minutes.*Preparation of buffer Weigh about 1.0 g of Potassium dihydrogenphosphate and dissolve in 1000 mL of water. Adjust the pH of thesolution to 6.00 ± 0.05 with 1N Sodium hydroxide preparation. Filter thebuffer through 0.45μ Durapore PVDF filter (Millipore). *Preparation oforganic Mix Methanol, Acetonitrile and Water in the modifier ratio of70:20:10 respectively.

TABLE 2 Gradient program Time (min) % Mobile phase-A % Mobile phase-B0.01 100 0 20 100 0 35 0 100 50 0 100 52 100 0 60 100 0

TABLE 3 Assay of Meloxicam injection by HPLC Chromatographic conditionsInstrument HPLC system equipped with UV/PDA- detector, binary/quaternarygradient pump, auto injector and suitable software Column Agilent ZorbaxEclipse XDB C18, 5μ (4.6 mm ID, × 150 mm) Pump mode Gradient Flow rate1.0 mL/minute Detector wavelength 350 nm Column oven 40° C. temperatureSample cooler 25° C. temperature Injection volume 10 μL Run time 25minutes Preparation of Mobile Prepare a mixture of Buffer** and organicphase-A modifier in the ratio of 70:30 (% v/v) and degas it for about 10minutes. Preparation of Mobile Prepare a mixture of Buffer and organicphase-B modifier in the ratio of 30:70 (% v/v) and degas it for about 10minutes. **Preparation of Buffer Weigh 1.36 g of Potassium dihydrogenphosphate and dissolve in 1000 mL of water. To this add 2 mL ofTriethylamine and mix well. Adjust the pH of the solution to 7.00 ± 0.05with dilute orthophosphoric acid. Filter the buffer through 0.45μDurapore PVDF filter (Millipore).

TABLE 4 Gradient program Time (minutes) % Mobile Phase-A % MobilePhase-B 0.01 100 0 12 0 100 17 0 100 18 100 0 25 100 0

EXAMPLES

The following examples are exemplary and not intended to be limiting.The above disclosure provides many different embodiments forimplementing the features of the invention, and the following examplesdescribe certain embodiments. It will be appreciated that othermodifications and methods known to one of ordinary skill in the art canalso be applied to the following experimental procedures, withoutdeparting from the scope of the invention.

Example 1

Meloxicam solution having composition was set forth in Table 5.

TABLE 5 Composition A Composition B Ingredients (Batch size - 200 mL)(Batch size - 250 mL) Meloxicam 7.5 mg  15 mg Meglumine 25 mg 25 mgWater for injection q.s. to 1 mL q.s. to 1 mL Hydrochloric acid q.s. foradjusting q.s. for adjusting pH to 8 pH to 8

Manufacturing procedure of Composition A and B: About 60% requiredquantity of water for injection was taken in two beakers (Beaker 1 and2). 5 and 6.25 grams of meglumine was added to the Beaker 1 and 2respectively and stirred for about 5-10 minutes at 500 RPM to obtainclear solutions. 1.5 and 3.75 grams of meloxicam was added to the clearsolutions of Beaker 1 and 2 respectively and stirred continuously foranother 60-80 minutes at 800-900 RPM. Sufficient quantities of water forinjection were added to make up volume to 200 mL in Beaker 1 and 250 mLin Beaker 2. pH of final solutions was adjusted to 8 using 0.1Nhydrochloric acid. Final solution in Beaker 1 and 2 were Composition Aand B respectively.

Stability data of Composition A and B were set forth in Table 6

TABLE 6 Composition A Composition B Storage — 25° C./ 40° C./ 2-8° C. —25° C./ 40° C./ Condition 60% RH 75% RH 60% RH 75% RH Duration Initial 6months 3 months Initial 6 months Visual Clear Clear Clear Clear ClearClear Clear observation of solution pH 8.01 7.89 7.67 8.07 8.41 8.488.45 Assay 103.2 102.8 103.1 101.9 99.1 101.1 100.6 Osmolality — 237 238238 232 218 219 Impurities (% w/w) Impurity-B 0.006 0.037 0.205 0.023 ND0.026 0.126 Unspecified 0.019 0.011 ND 0.017 0.015 0.043 0.039 impurity(1.580) (0.85) (1.69) (1.716) (1.65) (at RRT) Total 0.04 0.048 0.2050.06 0.042 0.102 0.21 impurities

Example 2

Meloxicam solution having composition was set forth in Table 7.

TABLE 7 Composition C Ingredients (Batch size - 150 mL) Meloxicam 25 mgMeglumine 45 mg Ethylenediaminetetraacetic 0.20 mg   acid (EDTA) Waterfor injection q.s. to 1 mL Hydrochloric acid (1N) q.s. for adjusting pHto 8

Manufacturing procedure of Composition C: About 60% required quantity ofwater for injection was taken in a beaker. 6.75 grams of meglumine and0.03 grams of EDTA were added to the beaker and stirred for about 5-10minutes at 500 RPM to obtain a clear solution. 3.75 grams of meloxicamwas added to the clear solution and stirred continuously for another60-80 minutes at 800-900 RPM. Sufficient quantity of water for injectionwas added to make up volume to 150 mL. pH of final solutions wasadjusted to 8 using 0.1N hydrochloric acid.

Samples of Composition C was stored at 25° C./60% RH and 40° C./75% RHfor 3 months, particles were observed after storing at 25° C./60% RH and40° C./75% RH for 3 months.

Stability data of Composition C was set forth in Table 8

TABLE 8 Composition C Storage Condition 25° C./ 40° C./ 60% RH 75% RHDuration Initial 3 months 3 months Visual observation Clear ParticlesParticles of solution observed observed pH 8.65 8.62 8.64 Assay 101.1103.7 100.3 Osmolality 383 387 389 Impurities (% w/w) Impurity-B ND0.031 0.165 Unspecified impurity 0.017 (1.718) 0.019 (0.446) 0.530(0.430) (at RRT) Total impurities 0.041 0.073 0.275

Example 3

Meloxicam solution having composition was set forth in Table 9.

TABLE 9 Composition D Ingredients (Batch size - 250 mL) Meloxicam 6 mgL-Arginine 5 mg HP-β-CD 90 mg  Water for injection q.s. to 1 mLHydrochloric acid q.s. for adjusting pH to 8

Manufacturing procedure of Composition D: About 125 mL of water forinjection was taken in a beaker. 1.25 grams of L-Arginine was added tothe beaker and stirred for about 15-20 minutes at 500 RPM to obtain aclear solution. 22.50 grams of HP-β-CD was added to the clear solutionand stirred for about 5-10 minutes at 500 RPM to obtain a clearsolution. 1.50 grams of meloxicam was added to the obtained solution andcontinued stirring for another 40-50 minutes at 800-900 RPM. Sufficientquantity of water for injection was added to make up volume to 250 mL.pH of final solutions was adjusted to 8 using 0.1 N hydrochloric acid.

Samples of Composition D was stored at 2-8° C. for 3 months, 25° C./60%RH and 40° C./75% RH for 6 months. Meloxicam solutions were clearwithout any particles after storing at 25° C.160% RH and 40° C.175% RHfor 6 months, and at 2-8° C. for 3 months.

Stability data of Composition D was set forth in Table 10

TABLE 10 Composition D Storage Condition — 25° C./60% RH 40° C./75% RH2-8° C. Storage duration Initial 3 months 6 months 3 months 6 months 3months Visual observation Clear Clear Clear Clear Clear Clear ofsolution pH 8.1 7.77 8.05 8.06 7.82 8.04 Assay 101.6 102 102.0 102.399.8 102.4 Osmolality 113 116 113 117 121 117 Impurities (% w/w)Impurity-B 0.006 0.015 0.042 0.105 0.358 0.016 Unspecified 0.021 0.0190.002 0.022 0.004 0.025 impurity (at RRT) Total impurities 0.04 0.070.044 0.15 0.362 0.07

Example 4

Meloxicam solution having composition was set forth in Table 11.

TABLE 11 Composition E Composition F Ingredients (Batch size - 100 mL)(Batch size -100 mL) Meloxicam 10 mg 30 mg Sodium dihydrogen 3.4 mg —phosphate monohydrate Disodium hydrogen 10.5 mg — phosphate anhydrousPEG-400 400 mg 180 mg  Meglumine — 20 mg Hydrochloric acid (1N) — q.s.for adjusting pH to 8.3 Water for Injection q.s. to 1 mL q.s. to 1 mL

Manufacturing procedure of Composition E and F: About 60% requiredquantity of water for injection was taken in two beakers (Beaker-1 andBeaker-2). 0.34 grams of sodium dihydrogen phosphate monohydrate wasadded to Beaker-1 and stirred to obtain a clear solution. 1.05 grams ofdisodium hydrogen phosphate anhydrous was added to clear solution ofBeaker-1 and stirred continuously to obtain a clear solution. 2 grams ofmeglumine was added to Beaker-2 and stirred for 5-10 minutes at 500 RPMto get a clear solution. 40 & 18 grams of PEG-400 was added to Beaker-1and Beaker-2 respectively and stirred at 500 RPM for almost 15 minutesto get a clear solution. 1 gm & 3 gm of meloxicam was added to eachBeaker-1 and Beaker-2 respectively and stirred at 800-900 RPM for 60-80minutes. Sufficient quantities of water for injection was added toBeaker-1 and 2 to make up volume to 100 mL. pH of Composition E was 7.pH of Composition F was adjusted to 8.3 by adding sufficient quantity of1N HCl.

Samples of Composition E was stored at 2-8° C., 25° C./60% RH and 40°C./75% RH for 3 months. Meloxicam solutions were clear without anyparticles after storing at 25° C./60% RH and 40° C./75% RH for 3 months.A dull white jelly like substance observed at the bottom of solutionwhen stored at 2-8° C. for 3 months.

Stability data of Composition E was set forth in Table 12

TABLE 12 Composition E Storage Condition 25° C./ 40° C./ — 60% RH 75% RH2-8° C. Storage duration Initial 3 months Visual observation Clear ClearClear A dull white jelly like of solution substance observed at thebottom pH 7.25 7.39 7.43 7.33 Assay 100.5 100.1 100.1 100.9 Impurities(% w/w) Impurity-B 0.027 0.154 0.446 0.016 Unspecified Impurity 0.024(0.681) 0.022 (0.62) 0.024 (0.98) 0.013 (1.69) (at RRT) Total impurities0.117 0.234 0.538 0.046

Example 5

Meloxicam solution having composition was set forth in Table 13.

TABLE 13 Composition G Composition H Ingredients (Batch size - 100 mL)(Batch size - 100 mL) Meloxicam 30.0 mg  30.0 mg Diethanolamine 150.0mg  150.0 mg Meglumine 25.0 mg — Hydrochloric q.s. for adjusting q.s.for adjusting acid (1N) pH to 8 pH to 8 Water for q.s. to 1 mL q.s. to 1mL Injection

Manufacturing procedure of Composition G and H: About 70% requiredquantity of water for injection was taken in two beakers (Beaker-1 & 2).15 g of diethanolamine was added to each of the Beaker-1 and Beaker-2;2.5 g of meglumine was added to Beaker-2 and were then stirred to obtainclear solutions. 3 g of meloxicam was added to the clear solutions ofeach beaker and stirred continuously for another 60-80 minutes at800-900 RPM. Sufficient quantity of water for injection was added toBeaker-1 and 2 to make up volumes to 100 mL. pH of solutions wasadjusted to 8 using 1N hydrochloric acid.

Example 6

Meloxicam solution having composition was set forth in Table 14.

TABLE 14 Composition Ingredients I J K L M N Batch size   150 mL   150mL   100 mL   100 mL   100 mL  50 mL Meloxicam  30.0 mg  30.0 mg  30.0mg  20.0 mg  15.0 mg  30 mg HP-β-CD 190.0 mg 220.0 mg 150.0 mg 100.0 mg100.0 mg 150 mg Meglumine  20.0 mg  20.0 mg  20.0 mg  20.0 mg  20.0 mg 20 mg TRIS — — — — —  12 mg HCL (1N) q.s. for adjusting pH to 8 Waterfor q.s. to q.s. to q.s. to q.s. to q.s. to q.s. to 1 Injection 1 mL 1mL 1 mL 1 mL 1 mL mL

Manufacturing procedure of Composition I, J, K, L, M and N: About 70%quantity of water for injection was heated to 50° C.-60° C. in was takenin six beakers (Beaker-1, 2, 3, 4, 5 & 6). 0.6 g of TRIS was added toBeaker-6 and stirred to obtain clear solution. Specified amount ofmeglumine was added to water for injection at 50° C.-60° C. and stirredcontinuously for 5 minutes at 500±50 RPM to obtain clear megluminesolution. Specified quantity of HP-β-CD was added to the megluminesolution and mixed continuously at temperature 50-60° C. for next 60minutes at 500±50 RPM to obtain clear HP-β-CD solution. Specifiedquantity of meloxicam was added to the HP-β-CD solution and mixedcontinuously at temperature 50-60° C. for the next 60 minutes at 500±50RPM to obtain clear meloxicam solution was kept for cooling to roomtemperature under continuous stirring. The remaining amount of water forinjection was added to the meloxicam solution to prepare final solution.pH of the final solutions was adjusted to 8 with 1N hydrochloric acid.

Samples of Composition I and J were stored for 3 months at 25° C./60% RHand at 40° C./75% RH. Meloxicam solutions were clear without anyparticles after storing at 25° C./60% RH and at 40° C./75% RH for 3months.

Stability data of Composition I and J was set forth in Table 15.

TABLE 15 Composition I Composition J Storage Initial 25°C./ 40°C./Initial 25°C./ 40°C./ Condition 60% RH 75% RH 60% RH 75% RH Storage 3months 3 months duration Visual Clear solution Clear solutionobservation of solution pH 8.05 8.11 8.10 8.06 8.05 8.06 Osmolality 338350 337 367 352 360 Assay 101.1 104.4 104.3 97.8 97.2 96.1 Impurities (%w/w) Impurity-B ND 0.020 0.125 ND 0.031 0.2 Unspecified 0.011 0.0150.015 0.014 0.019 0.012 Impurity (0.793) (1.68) (1.68) (0.794) (1.68)(1.68) (at RRT) Total 0.03 0.06 0.16 0.02 0.07 0.24 impurities

Samples of Composition L and M were stored for 7 days at 60° C.Meloxicam solutions were clear without any particles after storing at60° C. for 7 days.

Stability data of Composition L and M was set forth in Table 16.

TABLE 16 Composition L M Storage Condition 60° C.  Storage duration   7days Visual observation Clear Clear of solution pH 8.18 8 Assay 100.598.5 Osmolality 255 251 Impurities (% w/w) Impurity-B 0.119 0.094Unspecified Impurity 0.016 (0.80) 0.014 (0.80) (at RRT) Total impurities0.17 0.13

Samples of Composition K and N were stored at 60° C. for 7 days and for6 months at 25° C./60% RH and at 40° C./75% RH. Meloxicam solutions wereclear without any particles after storing at 60° C. for 7 days and at25° C./60% RH for 6 months. Tiny particles were observed in CompositionK and N when stored at 40° C./75% RH for 6 months

Stability data of Composition K and N was set forth in Table 17.

TABLE 17 Composition K Composition N Storage Initial 60° C. 25° C./ 40°C./ Initial 60° C. 25° C./ 40° C./ Condition 60% RH 75% RH 60% RH 75% RHStorage 7 days 6 months 7 days 6 months duration Visual Clear ClearClear Tiny Clear Clear Clear Tiny observation particles particles ofsolution pH 7.87 8.37 7.76 7.43 8.02 8.07 8.02 8.03 Assay 98.7 99.5 99.899.8 100.6 98.7 99.9 99.1 Osmolality 290 271 290 292 477 464 464 473Impurities (% w/w) Impurity-B 0.005 0.206 0.035 0.386 0.006 0.109 0.0450.316 Unspecified 0.019 0.017 0.013 0.022 0.019 0.015 0.012 0.020Impurity (1.69) (1.69) (1.71) (0.44) (0.80) (1.69) (1.71) (0.44) (atRRT) Total 0.05 0.25 0.08 0.46 0.06 0.15 0.09 0.39 impurities

Example 7

Animal Study: Evaluation of efficacy of meloxicam compositions in acutepost-operative pain (Brennan) model in Sprague Dawley rats.

The analgesic efficacy of Composition K was studied in comparison withAnjeso® and ketorolac tromethamine drug products in a rat acutepost-operative pain model at a dose of 3 mg/kg administered byintravenous route. Composition K has shown better trend compared toAnjeso® in terms of maximum efficacy and rate of analgesia development.Composition K have shown significant extended efficacy compared toAnjeso®.

Meloxicam compositions (Anjeso® & Composition K) & ketorolac drugproducts were tested in an acute post-operative (Brennan) pain model inrats after intravenous administration. Average paw withdrawal latency &mechanical hyperalgesia (pain assessment) parameters were assessed inrats after intravenous administration of vehicle (0.9% saline),ketorolac tromethamine (3 mg/kg), Anjeso® (3 mg/kg), Composition K (3mg/kg). Evaluations began 30 minutes following surgery, and werecontinued for 240 minutes.

Prior to surgery, mean paw withdrawal latency showed no statisticaldifference between any of the treatment groups. Mean paw withdrawallatency was between 8.6 to 8.9 across all the treatment groups. Aftersurgical incision all animals demonstrated increased mechanicalsensitivity with paw withdrawal latency threshold significantlydecreased compared normal control animals. Average paw withdrawallatency in normal animals is 9.7 seconds whereas as it was 3.5 secondsin operated animals.

Ketorolac tromethamine, Composition K and Anjeso® compositions whenadministered intravenously at 3 mg/kg dose significantly prevented thedevelopment of mechanical allodynia at from 45 minutes onwards till 240minutes of recording.

However statistically significant effect was observed at 45, 90 and 120minutes of recording.

Rats administered with ketorolac tromethamine (3 mg/kg; IV), CompositionK (3 mg/kg; IV) and Anjeso® (3 mg/kg; IV) showed 68%, 68% and 49%increased average paw withdrawal latency respectively when compared withrats administered with vehicle (0.9% saline).

FIG.1 discloses comparison of % change in average pain withdrawallatency in rats administered with test compounds (i.e., vehicle control(0.9% saline), ketorolac tromethamine (3 mg/kg; IV), Anjeso® (3 mg/kg;IV), Composition K (3 mg/kg; IV).

Example 8

Intravenous pharmacokinetics study of meloxicam compositions in maleSprague-Dawley rats

Plasma pharmacokinetics of meloxicam following a single intravenousadministration of two meloxicam compositions (i.e., Anjeso® andComposition K) to male Sprague-Dawley rats were investigated. The studywas performed using serial sampling design (n=6 rats/group) to obtaincomposite pharmacokinetics profile of meloxicam in male rats.

TABLE 18 Study design Concen- Dose tration Route/ Dose volume Test item(mg/mL) Group No. Gender (mg/kg) (mL/kg) Anjeso ® 30 IV/Group 1 Male 100.333 Composition 30 IV/Group 2 Male 10 0.333 K

Blood samples (200 μL/sample) were collected from external jugular veinat pre-determined time point from each rat post injection as follows:0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours (Total 8 bleedings/rat) forboth groups. The plasma samples were analyzed for the quantification ofmeloxicam in all three groups, using a fit-for purpose LC-MS/MS methodwith CC Range:100-50000(ng/mL).

TABLE 19 Mean plasma pharmacokinetic parameters of meloxicam followingsingle intravenous route of administration (ROA) of three differentformulations of Meloxicam in male Sprague-Dawley rats: Composition DoseC_(max) AUC_(last) AUCi_(nf) administered Group/ROA (mg/kg) (ng/mL)(h*ng/mL) (h*ng/mL) Anjeso ® Group 1/IV 10 72772 ± 555909 ± 1001610 ±6347.9 135829 570214 Composition Group 2/IV 10 53448 ± 435866 ± 634002 ±K 2795.7 97447.0 227624

Example 9

Meloxicam solution having composition was set forth in Table 20.

TABLE 20 Composition O Composition P Ingredients (Batch size - 100 mL)(Batch size - 100 mL) Meloxicam 30 mg 15 mg Meglumine 20 mg 20 mgPEG-300 200 mg  200 mg  Water for q.s. to 1 mL q.s. to 1 mL injection

Manufacturing procedure of Composition 0 and P: About 60% quantity ofthe water for injection was added and heated to 50° C.-60° C. in twobeakers. Specified quantities of meglumine was added to each beaker at50° C.-60° C. and stirred continuously for 5 minutes at 500±50 RPM toobtain clear meglumine solution. Specified quantities of meloxicam wasadded to each beaker at 50° C.-60° C. and stirred continuously for next60 minutes at 500±50 RPM to obtain clear meloxicam solution which waskept for cooling to room temperature under continuous stirring.Specified quantities of PEG-300 was added to each beaker and stirredcontinuously for next 60 minutes at 500±50 RPM to obtain clear pre-finalsolution. The remaining amount of water for injection was added topre-final solution to prepare final solution.

Samples of Composition 0 were stored at 60° C. for 22 days, and at 40°C./75% RH for 1 month. Meloxicam solutions were clear without anyparticles after storing at 60° C. for 22 days.

Samples of Composition P were stored at 60° C. for 30 days, and at 40°C./75% RH for 1 month. Meloxicam solutions were clear without anyparticles after storing at 60° C. for 22 days and at 40° C./75% RH for 1month.

Stability data of Composition 0 and P was set forth in Table 21.

TABLE 21 Composition O Composition P Storage Condition Initial 60° C.40° C./ Initial 60° C. 40° C./ 75% RH 75% RH Storage duration 22 days 1month 30 days 1 month Visual observation Clear solution Tiny Clearsolution of solution particles observed pH 8.87 — 8.97 9.73 — 9.73 Assay100.9 — 101.3 99.6 — 98.2 Osmolality 1732 1730 1722 1753 — 1757Impurities (% w/w) Impurity-B 0.025 0.23 0.051 0.016 — 0.042 Unspecified0.027 0.041 0.026 0.029 — 0.026 Impurity (at RRT) Total impurities 0.0610.46 0.088 0.041 — 0.068

Example 10

Meloxicam solution having composition was set forth in Table 22.

TABLE 22 Composition Q Composition R Ingredients (Batch size - 100mL/350 mL) (Batch size - 100 mL) Meloxicam 30 mg 30 mg Meglumine 20 mg20 mg HP-β-CD 150 mg  150 mg  Povidone K12 60 mg — WFI-Sterile q.s. to 1mL q.s. to 1 mL

Manufacturing procedure of Composition Q and R: About 60% quantity ofwater for injection was added and heated to 50° C.-60° C. in twobeakers. 2 g meglumine was added to Beaker-1 & 2 at 50° C.-60° C. andstirred continuously for 5 minutes at 500±50 RPM to get clear megluminesolutions. 15 g HP-β-CD was added to Beaker-1 & 2 at 50° C.-60° C. andstirred continuously for 5 minutes at 500±50 RPM to get clear HP-β-CDsolutions. 3 g meloxicam was added to Beaker-1 & 2 and were stirredcontinuously at temperature 50-60° C. for the next 60 minutes at 500±50RPM to obtain clear solutions which were allowed for cooling to roomtemperature under continuous stirring. 6 g Povidone K12 was added toBeaker-1 and stirred continuously for 15 minutes at 500±50 RPM to getpre-final solution. The remaining amount of water for injection wasadded to solutions of Beaker-1 & 2 to make up to 100 mL to prepare finalsolution. Final solutions in Beaker-1 & 2 are Composition Q and Rrespectively.

Samples of Composition Q were stored at 60° C. for 18 days, and at 40°C./75% RH for 1 month. Meloxicam solutions were clear without anyparticles after storing at 60° C. for 18 days, and at 40° C./75% RH for1 month.

Samples of Composition R were stored at 60° C. for 12 days, 25° C./60%RH for 1 month and at 40° C./75% RH for 1 month. Meloxicam solutionswere clear without any particles after storing at 60° C. for 18 days,25° C./60% RH for 1 month and at 40° C./75% RH for 1 month.

Stability data of Composition Q and R was set forth in Table 23.

TABLE 23 Composition Q Composition R Storage Initial 60° C. 25° C./ 40°C./ Initial 60° C. Condition results 60% RH 75% RH results Storage 1month 6 months 6 months 12 days duration Visual Clear solutionobservation of solution pH 9 8.9 8.98 8.91 9.6 NP Assay 100.6 99.2 98.698.7 101.4 NP Osmolality 370 NP 355 346 315 NP Impurities (% w/w)Impurity-B 0.014 0.271 0.034 0.093 ND 0.161 Unspecified 0.017 0.0210.013 0.027 0.029 0.024 Impurity (1.76) (0.623) (0.872) (0.079) (1.798)(at RRT) Total impurities 0.06 0.404 0.12 0.21 0.04 0.21 *ND═NotDetected; NP═Not Performed

Terminal sterilization data of Composition Q was set forth in Table 24.

TABLE 24 Composition Q Sterilization method Autoclave at 121° C.Autoclave at 121° C. Storage duration 15 minutes 18 minutes Visualobservation Clear solution Clear solution of solution pH 8.99 8.97 Assay102.4 100.5 Osmolality (Osmol/Kg) 430 428 Impurities (% w/w) Impurity-B0.264 0.272 Oxalate Impurity 0.009 0.009 Unspecified Impurity 0.095(0.081) 0.103 (0.081) (at RRT) Total impurities 0.475 0.498

Example 11

Meloxicam solution having composition was set forth in Table 24.

TABLE 24 Composition S T U V W Batch size Ingredients 350 mL 350 mL 350mL 350 mL 350 mL Meloxicam 30 mg 30 mg 30 mg 20 mg 15 mg Meglumine 20 mg20 mg 20 mg 15 mg 10 mg PEG-300 100 mg  80 mg 50 mg 100 mg  100 mg Povidone 10 mg 10 mg 10 mg 10 mg 10 mg K12 Water for q.s. to q.s. toq.s. to q.s. to q.s. to injection 1 mL 1 mL 1 mL 1 mL 1 mL

Manufacturing Procedures of Composition S, T, U, V and W: About 60% ofwater for injection was added and heated to 50° C.-60° C. in fivebeakers. Specified quantity of meglumine was added to beakers at 50°C.-60° C. and stirred continuously for 5 minutes at 500±50 RPM to getclear meglumine solutions. Specified quantity of meloxicam was added tobeakers and were stirred continuously at temperature 50-60° C. for thenext 60 minutes at 500±50 RPM to obtain clear solutions which wereallowed for cooling to room temperature under continuous stirring.Specified quantity of Povidone K12 was added to beakers and stirredcontinuously for 15 minutes at 500±50 RPM to get povidone solutions.Specified quantity of PEG-300 was added to povidone solutions and mixedcontinuously for 15 minutes at 500±50 RPM to obtain clear pre-finalsolutions. The remaining quantity of water for injection was added topre-final solutions to prepare final solutions.

Samples of Composition S, V and W were stored at 60° C. for 14 days(14D), 25° C./60% RH for 1 month (1M) and at 40° C./75% RH for 1 month(1 M). Meloxicam solutions were clear without any particles afterstoring at 60° C. for 14 days (14D), 25° C./60% RH for 1 month (1M) andat 40° C./75% RH for 1 month (1M).

Stability data of Composition S and V was set forth in Table 25 and Wwas set forth in Table 26.

TABLE 25 Composition S Composition V Storage Initial 60° C. 25° C./ 40°C./ Initial 60° C. 25° C./ 40° C./ Condition 60% RH 75% RH 60% RH 75% RHStorage 14D 1M 1M 14D 1M 1M duration Visual Clear solution Clearsolution observation of solution pH 9 8.99 8.99 8.97 9.18 9.15 9.19 9.19Assay 100.1 103.8 100.8 100.7 102 101.5 102.2 102.1 Osmolality 661 670658 657 626 631 619 620 Impurities (% w/w) Impurity-B 0.012 0.23 0.0250.041 0.012 0.23 0.025 0.040 Unspecified 0.015 0.032 0.024 0.015 0.0150.034 0.016 0.014 Impurity (1.76) (1.76) (at RRT) Total 0.06 0.347 0.1040.091 0.05 0.349 0.068 0.079 impurities

TABLE 26 Composition W Storage Condition 25° C./ 40° C./ 60° C. 60% RH75% RH Storage duration Initial 14 days 1 M 1 M Visual observation Clearsolution of solution pH 9.02 9.01 9.01 9.04 Assay 102.3 101.2 102.3101.9 Osmolality 593 595 588 585 Impurities (% w/w) Impurity-B 0.0140.26 0.034 0.053 Unspecified Impurity 0.017 (1.76) 0.043 0.016 0.013 (atRRT) Total impurities 0.06 0.37 0.085 0.108

Example 12

Meloxicam solution having composition was set forth in Table 27.

TABLE 27 Composition X Composition Y Composition Z Batch sizeIngredients 500 mL 50 mL 50 mL Meloxicam 30 mg 30 mg 30 mg Meglumine 20mg 20 mg 20 mg PEG-400 100 mg  80 mg 50 mg Povidone K12 10 mg 10 mg 10mg Water for injection q.s. to 1 mL q.s. to 1 mL q.s. to 1 mL

Manufacturing Procedures of Composition X, Y and Z: About 60% quantityof the water for injection was added and heated to 50° C.-60° C. inthree beakers. Specified quantities of meglumine was added to eachbeaker at 50° C.-60° C. and stirred continuously for 5 minutes at 500±50RPM to obtain clear meglumine solution. Specified quantities ofmeloxicam was added to each beaker at 50° C.-60° C. and stirredcontinuously for next 60 minutes at 500±50 RPM to obtain clear meloxicamsolution which was kept for cooling to room temperature under continuousstirring. Specified quantities of Povidone K12 was added to each beakerand stirred continuously for next 15 minutes at 500±50 RPM to obtainclear povidone solution. Specified quantities of PEG-400 was added toeach beaker and stirred continuously for next 5 minutes at 500±50 RPM toobtain clear pre-final solution. The remaining amount of water forinjection was added to pre-final solution to prepare final solution.

Stability data of Composition X, Y and Z was set forth in Table 28.

TABLE 28 Composition X Storage Condition 25° C./ 40° C./ 60% RH 75% RHStorage duration Initial 1 month 1 month Visual observation Clearsolution of solution pH 8.97 8.97 8.97 Assay 100.2 98.0 98.1 Osmolality567 560 568 Impurities (% w/w) Impurity-B 0.01 0.026 0.057 UnspecifiedImpurity 0.016 0.015 0.013 (at RRT) Total impurities 0.028 0.073 0.116

Example 13

Meloxicam solution having composition was set forth in Table 29.

TABLE 29 Composition ZA Composition ZB Composition ZC Batch sizeIngredients 50 mL 350 mL 350 mL Meloxicam 30 mg 30 mg 30 mg Meglumine 20mg 20 mg 20 mg PEG-300 100 mg  80 mg 50 mg Povidone 10 mg 10 mg 10 mgK12 Hydrochloric pH adjusted — — acid (1N) to 8.0 Water for q.s. to 1 mLq.s. to 1 mL q.s. to 1 mL injection

Manufacturing Procedure of Compositions ZA, ZB and ZC: About 60%quantity of water for injection was heated to 50° C.-60° C. in asuitable container. Specified amount of meglumine was added to thepurified water at 50° C.-60° C. and stirred continuously for 5 minutesat 500±50 RPM or until a clear solution is obtained to get megluminesolution. Specified quantity of meloxicam was added to the megluminesolution and mixed continuously at temperature 50-60° C. for next 60minutes at 500±50 RPM or until a clear solution was obtained to getmeloxicam solution which was allowed for cooling to room temperatureunder continuous stirring. Specified quantity of Povidone K12 was addedto the meloxicam solution and mixed continuously for 15 minutes at500±50 RPM or until a clear solution was obtained to get povidonesolution. Specified quantity of PEG-400 was added to povidone solutionand mixed continuously for 5 minutes at 500±50 RPM or until a clearsolution is obtained to get pre-final solution. The remaining amount ofwater for injection was added to the pre-final solution to prepare finalsolution. For the Composition ZA, the pH of the final solution wasadjusted to 8 with 1N hydrochloric acid.

Example 14 Intravenous Pharmacokinetics Study of Meloxicam Compositionsin Male Sprague-Dawley Rats

Plasma pharmacokinetics of meloxicam following a single intravenousadministration of two meloxicam compositions (i.e., Anjeso® andComposition Q) to male Sprague-Dawley rats were investigated. The studywas performed using serial sampling design (n=8 rats/group) to obtaincomposite pharmacokinetics profile of meloxicam in male rats.

TABLE 31 Study design Concen- Dose tration Route/ Dose volume Test item(mg/mL) Group No. Gender (mg/kg) (mL/kg) Anjeso ® 30 IV/Group 1 Male 100.333 Composition Q 30 IV/Group 2 Male 10 0.333

Blood samples (200 μL/sample) were collected from external jugular veinat pre-determined time point from each rat post injection as follows:0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8, 24, 48, 72 and 96 hours (Total 12bleedings/rat) for both groups. The plasma samples were analyzed for thequantification of meloxicam in both groups, using a fit-for purposeLC-MS/MS method with CC Range:100-50000(ng/mL).

Table 32

Mean plasma pharmacokinetic parameters of meloxicam following singleintravenous route of administration (ROA) of two different formulationsof Meloxicam in male Sprague-Dawley rats.

TABLE 32 Composition Dose C₀ AUC_(last) AUCi_(nf) administered Group/ROA(mg/kg) (ng/mL) (h*ng/mL) (h*ng/mL) Composition Q Group 1/IV 10 1060001730000 1930000 (Test) Anjeso ® Group 2/IV 10 97900 1420000 1740000(Reference)

In conclusion, the Composition Q had showed comparable pharmacokineticsprofile with that of ANJESO® following a single intravenous route ofadministration in Male Sprague-Dawley rats. Test/Reference ratio wasfound to be 1.08, 1.22 and 1.11 for C₀ (ng/mL), AUC_(last(h·ng/mL)) andAUC_(inf) (h·ng/mL) respectively.

Having now fully described this invention, it will be understood bythose of ordinary skill in the art that it can be performed within awide equivalent range of parameters without affecting the scope of theinvention or any embodiment thereof. All publications, patentapplications and patents disclosed herein are incorporated by referencein their entirety.

1. A composition comprising a stable solution of meloxicam suitable forparenteral administration comprising: (a) a therapeutically effectiveamount of meloxicam, (b) one or more pharmaceutically acceptablesolvents; (c) one or more solubilizers; (d) optionally, a nucleationinhibitor; and optionally, one or more other pharmaceutically acceptableexcipients.
 2. The composition according to claim 1, wherein thesolution has a pH in the range of about 5 to about
 12. 3. Thecomposition according to claim 1, wherein the solution has an osmolalityvalue of between about 100 mOsm and about 2000 mOsm.
 4. The compositionaccording to claim 1, wherein the solubilizers are selected from a groupcomprising meglumine, cyclodextrin, cyclodextrin derivative,monoethanolamine, diethanolamine, tromethamine, hydroxypropyl methylcellulose (HPMC), L-arginine, L-lysine, polysorbate 80 (Tween® 80),polysorbate 20 (Tween® 20), poloxamer, propylene glycol, glycerin,ethanol, polyethylene glycol (300 and 400), sorbitol, dimethylacetamide,and polyethoxylated castor oil (Cremophor® EL) or mixtures thereof. 5.The composition according to claim 1, wherein the nucleation inhibitoris selected from polyvinylpyrrolidone (PVP), crospovidone, hydroxypropylmethyl cellulose (HPMC), polysorbate, phospholipids such asdimyristoylphosphatidyl glycerol (DMPG),disteroylphosphatidylethanolamine (DSPE), 1,2-Distearoyl phosphatidylethanolamine methyl-polyethylene glycol conjugate (DSPE-mPEG), or anycombination thereof.
 6. The composition of claim 1, wherein saidmeloxicam solution stored for 6 months at 40° C./75% RH has an amount of2-Amino-5-methylthiazole that is less than about 0.2% w/w of meloxicamof the total composition.
 7. A composition comprising a stable solutionof meloxicam suitable for parenteral administration comprising: (a) atherapeutically effective amount of meloxicam, (b) one or morepharmaceutically acceptable solvents; (c) one or more solubilizers; (d)optionally, one or more other pharmaceutically acceptable excipients,and wherein a subject administered with said composition exhibitsincreased average paw withdrawal latency when compared to a subjectadministered with reference composition.
 8. The composition according toclaim 7, wherein the subject is a rat or a human.
 9. The compositionaccording to claim 7, wherein said composition stored for 6 months at40° C./75% RH has an amount of 2-Amino-5-methylthiazole that is lessthan about 0.2% w/w of meloxicam of the total composition.
 10. Acomposition comprising a stable solution of meloxicam suitable forparenteral administration comprising: (a) a therapeutically effectiveamount of meloxicam, (b) one or more pharmaceutically acceptablesolvents; (c) one or more solubilizers; and (d) optionally, a nucleationinhibitor; (e) optionally, one or more other pharmaceutically acceptableexcipients, wherein said composition upon administration exhibits abioequivalence to a reference composition; and wherein saidbioequivalence is established by at least one of: (i) a confidenceinterval for mean AUC_(0-t) between about 80% and about 125%; (ii) aconfidence interval for mean AUC_(0-infinity) between about 80% andabout 125%; (iii) a confidence interval for mean C_(max) between about80% and about 125%.
 11. A method of treating pain by parenterallyadministering to a patient in need thereof a composition comprising astable solution of meloxicam, wherein said solution provides rapid onsetof action for pain relief compared to a reference composition.
 12. Themethod of claim 11, wherein said composition comprises meloxicam in asolubilized form.
 13. The method of claim 11, wherein said compositioncomprises meloxicam, one or more solubilizers; a nucleation inhibitor;one or more pharmaceutically acceptable solvents; and optionally one ormore other pharmaceutically acceptable excipients.
 14. The method ofclaim 13, wherein the meloxicam dose is 30 mg.
 15. The method of claim13, wherein the solubilizer is selected from a group comprisingmeglumine, cyclodextrin, cyclodextrin derivative, monoethanolamine,diethanolamine, tromethamine, hydroxypropyl methyl cellulose (HPMC),L-arginine, L-lysine, polysorbate 80 (Tween® 80), polysorbate 20 (Tween®20), poloxamer, propylene glycol, glycerin, ethanol, polyethylene glycol(300 and 400), sorbitol, dimethylacetamide, and polyethoxylated castoroil (Cremophor® EL) or combinations thereof.
 16. The method of claim 13,wherein the nucleation inhibitor is povidone.
 17. The method of claim11, wherein the administration of said composition provides the patienta rapid onset of pain relief without the use of a second NSAID.
 18. Thecomposition of claim 1, wherein said meloxicam solution stored for 1month at 40° C./75% RH has an amount of 2-Amino-5-methylthiazole that isless than about 0.2% w/w of meloxicam of the total composition.
 19. Themethod of claim 11, wherein said composition stored for 6 months at 40°C./75% RH has an amount of 2-Amino-5-methylthiazole that is less thanabout 0.2% w/w of meloxicam of the total composition.
 20. The method ofclaim 11, wherein said composition stored for 1 month at 40° C./75% RHhas an amount of 2-Amino-5-methylthiazole that is less than about 0.2%w/w of meloxicam of the total composition.